Microarray Analysis of the Gene Expression Profile in

1368 © 2018 Nigerian Journal of Clinical Practice | Published by Wolters Kluwer ‑ Medknow

Objective: Triethylene glycol dimethacrylate (TEGDMA) is an important resin monomer commonly used in the structure of dental restorative materials. Recent studies have shown that unpolymerized resin monomers may be released into the oral environment and cause harmful biological effects. We investigated changes in the gene expression profiles of TEGDMA‑treated human dentalpulp cells (hDPCs) following short‑ (1‑day) and long‑term (7‑days) exposure. Materials and Methods: HDPCs were exposed to a noncytotoxic concentration ofTEGDMA,andgeneexpressionprofileswereevaluatedbymicroarrayanalysis.The resultswereconfirmedbyquantitative reverse‑transcriptasePCR(qRTPCR).Results: In total, 1282 and 1319 genes (up‑ or down‑regulated) were differentially expressed compared with control group after the 1‑ and 7‑day incubation periods, respectively. Biological ontology‑based analyses revealed that metabolic, cellular, and developmental processes constituted the largest groups of biological functional processes. qRT‑PCR analysis on bone morphogenetic protein‑2 (BMP‑2), BMP‑4, secreted protein, acidic, cysteine‑rich, collagen type I alpha 1, oxidative stress‑induced growth inhibitor 1, MMP3, interleukin‑6, and heme oxygenase‑1 genes confirmed the changes in expression observed in the microarray analysis.Conclusions: Our results suggest that TEGDMA can change the many functions of hDPCs through large changes in gene expression levels and complex interactions with different signaling pathways.

Keywords: Gene expression, human dental pulp cell, microarray, triethylene glycol dimethacrylate

Microarray Analysis of the Gene Expression Profile in Triethylene Glycol Dimethacrylate-treated Human Dental Pulp CellsD Torun, ZÖ Torun1, K Demirkaya1, M Sarper2, MP Elçi2, F Avcu2,3

Address for correspondence: Dr. ZÖ Torun, Department of Restorative Dentistry and Endodontics, Gulhane

Military Medical Academy, Etlik, Ankara 06018, Turkey. E‑mail: [email protected]

Various studies have been performed to show the adverse biological effects of TEGDMA on different mammalian cells. Previous studies revealed that TEGDMA has considerable cytotoxicity against different cell types via DNA damage, caspase activation, induction of apoptotic proteins, and reactive oxygen species.[4‑10] TEGDMA also influences the odontogenic differentiation capacityof dental pulp cells by decreasing the expression of mineralization‑related genes.[11] TEGDMA can cause changes in the immune system by affecting cytokine

Original Article

Introduction

Resin monomers are widely used in dentin bonding agents and composite resins to restore teeth structures

impaired by caries or fractures. With its hydrophilic structure and low molecular weight, triethylene glycol dimethacrylate (TEGDMA) is an important resin monomer and undergoes rapid polymerization after light curing. Due to its hydrophilic nature, the degradation processes and insufficient polymerization of TEGDMAcause the release of dental resin monomers into the oral environment, which can trigger hazardous biological effects on living oral tissues.[1,2] Dentin thickness and the severity of the caries lesion are important factors in determining the amount of resin monomers interacting with dental pulp tissue.[3]

Departments of Medical Genetics, 1Restorative Dentistry and Endodontics, 2Medical and Cancer Research Center and 3Haematology, Gulhane Military Medical Academy, Ankara 06018, Turkey

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How to cite this article: Torun D, Torun ZÖ, Demirkaya K, Sarper M, Elçi MP, Avcu F. Microarray analysis of the gene expression profile in triethylene glycol dimethacrylate-treated human dental pulp cells. Niger J Clin Pract 2017;20:1368-403.

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DOI: 10.4103/1119-3077.181353

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Date of Acceptance: 06-Apr-2016

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Torun, et al.: mRNA profiles of TEGDMA‑treated human pulp cells

1369Nigerian Journal of Clinical Practice ¦ Volume 20 ¦ Issue 11 ¦ November 2017

production and the expression of surface markers that are essential for immune cells.[12,13] These findingssuggest that TEGDMA interacts with living cells by influencing different biological pathways and causingadverse effects.

Recently, high‑throughput procedures such as DNA microarray and RNA‑seq technologies have been used to investigate the effects of high and low doses of TEGDMA on skin fibroblasts and human dental pulpcells (hDPCs), respectively.[9.11] These studies have greatly contributed to scientificknowledge regarding thebasic mechanisms of action of TEGDMA, but unknown issues remain to be determined. Microarray analysis can be used to decipher the expression state of tens of thousands of genes in a single experiment. Microarrays provide an opportunity to explore the effects of various materials and allow researchers to evaluate the overall state of a cell. In addition, gene ontology databases contribute to the understanding of predominant biological processes, pathways, and functional regulatory networks from the microarray data.

In the present study, we tested the hypothesis that an increase in the exposure time of hDPCs to TEGDMA may differentially alter the gene expression profileof hDPCs. Thus, hDPCs and high‑throughput DNA microarray analysis were used to test whether TEGDMA changed gene expression profiles after 1‑ and 7‑dayexposure periods.

Materials and MethodsCell cultureThis study was approved by the local Ethics Committee. Dental pulp tissues were obtained from the molars of healthy patients undergoing orthodontic treatments. Extracted molars were kept in phosphate‑buffered saline solution (Biological Industries, Kibbutz Beit Haemek, Israel) containing 100 U/mL penicillin and 100 µg/mL streptomycin (Biological Industries) to eliminate bacterial contamination. After transferring to the laboratory, extracted molars were cut horizontally 1 mm below the cementoenamel junction. The pulp tissues were gently separated from the crown and root and placed in a 100‑mm Petri dish. Pulp tissues were cut into small pieces with a blade and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM; BiologicalIndustries) containing 10% fetal bovine serum (FBS; Biological Industries), 100 U/mL penicillin, and 100 µg/mL streptomycin (Biological Industries). Tissue culturesweremaintained in ahumidified atmosphereof5% CO2at37°C.Cellsfromthefifthpassagewereusedfor subsequent experiments and cultured for 24 h before analysis.

XTT assayThe XTT assay was used to determine the noncytotoxic dose of TEGDMA. The XTT assay is useful for determining cellular proliferation and viability by spectrophotometric quantification. The assay is used tomeasure cell proliferation in response to growth factors, cytokines, and nutrients based on the conversion of the yellow tetrazolium salt 2,3‑bis‑(2‑methoxy‑4‑nitro‑5‑sulfophenyl)‑2H‑tetrazolium‑5‑carboxanilide) to an orange formazan dye by metabolically active and viable cells. Cells (100 µL/well) were seeded into 96‑well plates at 2 × 104perwellandincubatedfor24hinahumidifiedatmosphere of 5% CO2 at 37°C. Then, three groups were prepared: 0.3 mm TEGDMA, 1 mm TEGDMA, and 3 mm TEGDMA. TEGDMA was purchased from Sigma‑Aldrich (Sigma Chemical Company, St. Louis, MO, USA). Untreated cell cultures were used as control. The cell cultures were exposed to serial dilutions of the test materials. After an incubation period of 7 days, 50 µL (0.3 mg/mL) of XTT labeling mixture (Cell Proliferation Kit II; Roche, Mannheim, Germany) was added to each well, followed by incubation for 4 h in a humidified atmosphere of 5% CO2 at 37°C. The absorbances of the metabolized media were measured at 450 nm using a microplate reader (ELX800BKT, Bio‑Tek Instruments, USA). Cell viabilities of the test groups were calculated as a percentage of the control group. Each experimental group consisted of nine samples.

Microarray analysisThe TEGDMA concentration to be used for microarray analysis was decided by determining where it exhibited significantly different (P < 0.05) but higher cell viability (>90%) after 7 days. Thus, 1 mm TEGDMA was selected as the experimental dosage. hDPCs were seeded into 12‑well plates at 1 × 106 per well and incubated for 24 h in a humidified atmosphere of 5% CO2 at 37°C. Cells were pooled 1; 7 days after, 1 mm TEGDMA was applied. Cell pooling was conducted from 3 wells of each group. Wells without TEGDMA were also cultured for 1 and 7 days, and untreated hDPCs were used as controls. Each experimental group consisted of four samples.

Total RNA from hDPCs was extracted using the RNeasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer’s instructions. RNA purity and integrity were quantified using a p360 Nanophotometer(Implen, Germany). The microarray analysis was performed using the GeneChip 3 IVT Express Kit(Affymetrix,USA).Briefly,totalRNAwassubjectedto reverse transcription (first‑strand cDNA synthesis),converted into double‑strand cDNA, in vitro transcription, purification, and fragmentation. The samples werehybridized onto the GeneChip PrimeView Human Gene



1370 Nigerian Journal of Clinical Practice ¦ Volume 20 ¦ Issue 11 ¦ November 2017

Expression Array (Affymetrix), which covers more than 36,000 transcripts and variants. After hybridization for 16 h at 45°C, the arrays were washed and then scanned to obtain quantitative gene expression levels.

Data were analyzed using the Expression Console and Transcriptome Analysis Console/Partek Genomic Suite. Raw data were normalized by the robust multiarray average algorithm.Array datawere filtered by detection P < 0.05. A comparative analysis between each sample was carried out using fold‑change data. Biological, ontology‑based analyses were conducted using the PANTHER database (http://www.pantherdb.org).

Quantitative real‑time PCR (qRT‑PCR) analysisTo confirm the results obtained from the microarrayexperiments, qRT‑PCR was performed. Bone morphogenetic protein‑2 (BMP‑2), BMP‑4, secreted protein, acidic, cysteine‑rich (SPARC), collagen type I alpha 1 (COL1A1), oxidative stress‑induced growth inhibitor 1 (OSGIN1), matrix metallopeptidase‑3 (MMP-3), interleukin‑6 (IL-6), and heme oxygenase‑1 (HMOX1) genes were chosen due to their relationship with mineralization, bone formation, extracellular matrix (ECM) formation, DNA damage, oxidative stress, apoptosis, and inflammation,respectively.β‑actin(ACTB)wasusedasahousekeepinggene to normalize RNA expression. qRT‑PCR analyses were conducted using the total RNA samples previously described for the microarray analyses. cDNA was synthesized from 25 ng of total RNA using the Transcriptor High Fidelity cDNA Synthesis Kit (Roche). The cDNA obtained was used as a template for PCR. The target cDNA was then amplified using specificprimer pairs [Table 1]. qRT‑PCR was performed using the Faststart Essential DNA Green Master (Roche) and a LightCycler Nano Instrument (Roche).

The 20‑μL reaction mixture consisted of 5 μL cDNA,4 μL water, 10 μL × 2 master mix buffer, and a finalconcentrationof0.25pmol/μLofeachprimer.qRT‑PCRconditions included an initial denaturation step at 95°C for 10 min, followed by 45 cycles at 95°C for 10 s, 60°C for 10 s, and 72°C for 10 s. The mRNA level in each sample was calculated using ΔΔCT (i.e., ΔCT[treatedsample]−ΔCT[untreatedsample])method.Eachexperiment was performed in triplicate.

Statistical analysisSPSS software (version 21.0; IBM, Chicago, IL, USA) was used for all calculations. The distributions of all numerical variables, including BMP-2, BMP-4, SPARC, COL1A1, OSGIN-1, MMP-3, IL-6, and HMOX1 mRNA levels, were skewed; thus, results were reported as medians and interquartile ranges. The Mann–Whitney

U‑test was used to compare numerical variables between groups. A P < 0.05 was considered statistically significant.

ResultsMicroarray data analysesOnly genes showing expression changes >2‑fold after 1 mm TEGDMA treatment were taken into consideration. In total, 1282 and 1319 genes (up‑ or down‑regulated) were differentially expressed compared with control group after 1‑ and 7‑day incubationw periods, respectively. Of these, 276 genes were upregulated and 521 were downregulated in both time periods. Also, 481 and 518 genes exhibited statistically significantdifferential expression (up‑ or down‑regulated) solely after 1‑ or 7‑day incubation period, respectively. Transcripts with altered expression levels and biological, ontology‑based analyses are reported in Supplementary Tables 1 and 2.

The largest groups of upregulated genes were involved in metabolic processes (GO: 0008152), cellular processes

Figure 1: Diagram of the largest groups of upregulated biological processes in triethylene glycol dimethacrylate‑treated human dental pulp cells after (a) 1‑ and (b) 7‑day incubation period. The numbers designated in the pieces represent the number of genes those appear in any given category

b

a




(GO: 0009987), developmental processes (GO: 0032502), localization (GO: 0051179), biological regulation (GO: 0065007), responses to stimuli (GO: 0050896), immune system processes (GO: 0002376), cellular component organization or biogenesis (GO: 0071840), biological adhesion (GO: 0022610), apoptotic processes (GO: 0006915), reproduction (GO: 0000003), and growth (GO: 0040007) [Figure 1]. The largest groups of downregulated genes were involved in metabolic processes (GO: 0008152), cellular processes (GO: 0009987), developmental processes (GO: 0032502), biological regulation (GO: 0065007), multicellular organismal processes (GO: 0032501), immune system processes (GO: 0002376), localization (GO: 0051179), responses to stimuli (GO: 0050896), biological adhesion

(GO: 0022610), cellular component organization or biogenesis (GO: 0071840), apoptotic processes (GO: 0006915), reproduction (GO: 0000003), locomotion (GO: 0040011), and growth (GO: 0040007) [Figure 2].

The genes that showed expression changes >10‑fold are listed in Table 2. The THBD gene exhibited the highest expression level, with 88.54‑ and 57.65‑fold changes after 1‑ and 7‑day incubation periods, respectively. The COL1A1 and FDNC1 genes showed the most dramatic downregulation,with−57.48‑and−128.02‑foldchanges,respectively.

qRT‑PCR validationThe microarray data were validated using qRT‑PCR on the following genes: BMP-2, BMP-4, SPARC, COL1A1,

Table 1: Primer sequence list in qRT-PCRTarget gene

Primer sequence Annealing temperature (°C)

BMP-2 F:5’‑ CGGACTGCGGTCTCCTAA ‑3’ 60R:5’‑ GGAAGCAGCAACGCTAGAAG ‑3’

BMP-4 F:5’‑ ATGTGGGCTGGAATGACTGG ‑3’R:5’‑ GCACAATGGCATGGTTGGTT ‑3’

SPARC F:5’‑ TGCAATGTGTTAGGGGATCTT ‑3’R:5’‑ TGGTCTGCCTGCTAGAATGTT ‑3’

COL1A1 F:5’‑ CCCAGCCACCTCAAGAGAAG ‑3’R:5’‑ GTTCTCGATCTGCTGGCTCA ‑3’

OSGIN1 F:5’‑ CTATGAGGGTTACCGCAGCC ‑3’F:5’‑ AGACCCCAAACACCTTCTCG ‑3’

MMP-3 F:5’‑ CAAAACATATTTCTTTGTAGAGGACAA ‑3’R:5’‑ TTCAGCTATTTGCTTGGGAAA ‑3’

IL-6 F:5’‑ CAGGAGCCCAGCTATGAACT‑3’R:5’‑ GAAGGCAGCAGGCAACAC‑3’

HMOX1 F:5’‑ CAGTCAGGCAGAGGGTGATAG‑3’R:5’‑ AGCTCCTGCAACTCCTCAAA‑3’

β‑Actin F:5’‑ ACTCTTCCAGCCTTCCTTCC ‑3’R:5’‑ CGTACAGGTCTTTGCGGATG ‑3’

BMP-2=Bone morphogenetic protein‑2; BMP-4=Bone morphogenetic protein‑4; SPARC=Secreted protein, acidic, cysteine‑rich; COL1A1=Collagen type I alpha 1; OSGIN1=Oxidative stress‑induced growth inhibitor 1; MMP-3=Matrix metallopeptidase‑3; IL-6=Interleukin‑6; HMOX1=Heme oxygenase‑1

Table 2: Genes those showed up- and down-regulation of more than 10-fold changes after 1 mm triethylene glycol dimethacrylate treatment

Incubation period Upregulated Downregulated1 day AGPAT9, ANGPTL4, AREG,

CLGN, DNER, GNLY, IL13RA2, KCNN4, MMP10, MMP12, PTGS1, SERPINB2, STC1, TFPI2, THBD

ASPN, CCL8, CNN1, COL11A1, COL14A1, COL15A1, COL1A1, COL3A1, CXCL12, CXCL6, DSP, EFEMP1, ELOVL2, FMOD, FNDC1, IGF2, IGFBP3, IGFBP5, NREP, PAPPA, PDGFD, PLXNC1, PMEPA1, POSTN, RBMS3, RHOBTB1, RNF150, SORBS2, SULF2, VCAM1, VCAN, WFDC1

7 days CCDC68, DKK1, DNER, EREG, IL13RA2, KCNN4, KRTAP1‑5, NPTX1, SERPINB2, TFPI2, THBD

ADAMTS5, ASNS, ASPN, BCAT1, CALD1, CCL8, CCL11, CH25H, CNN1, COL11A1, COL14A1, COL15A1, COL1A1, CSTA, CXCL12, ECM2, EFEMP1, EGFL6, FMOD, FNDC1, HEPH, HMCN1, IGF2, IGFBP3, IGFBP5, MAF, MFAP4, OLFML3, PAPPA, PLXNC1, PMEPA1, POSTN, PTGDS, RHOBTB1, SAMD5, SCD, SORBS2, SULF2, TAGLN, TENM2, VCAN, WFDC1

The underlined genes represent the highest fold changes




OSGIN-1, MMP-3, IL-6, and HMOX1. These eight genes are related to mineralization, bone formation, ECM formation, DNA damage, oxidative stress, apoptosis, and inflammation. qRT‑PCR results are shown in Figure 3.TheqRT‑PCRresultsconfirmedthechangesinexpressionrevealed by the microarray analysis. hDPCs treated with 1 mm TEGDMA showed increased expression levels of BMP-2, OSGIN-1, MMP-3, and HMOX1, and decreased expression of BMP-4, SPARC, COL1A1, and IL-6 (all P < 0.05) compared with control group.

DiscussionResin monomers are used quite widely in dental practice. However, monomers cause many adverse biological effects in exposed cells and disturbance in many regulatory cellular mechanisms in cells interacting with some of these monomers. Previous studies have used high‑throughput technologies such as DNA microarray and RNA‑seq to investigate the biological effects of TEGDMA on skin fibroblasts and hDPCs,respectively.[9,11] These studies revealed that TEGDMA

leads to considerable gene expression changes over time and affects many different signaling pathways. However, the effects of TEGDMA interacting with hDPCs over a relatively long time period are not understood. Knowledge of the cellular mechanisms associated with the adverse effects of TEGDMA will provide a better understanding to improve materials being used and may lead to innovative therapeutic strategies. In this study, we sought to determine the effects of TEGDMA on hDPCs after a 7‑day exposure period. The results of this study confirmed a highly variable gene expression profile ofhDPCs after exposure to TEGDMA and the capacity of TEGDMA to induce DNA damage, oxidative stress, apoptosis, inflammation, and negative regulation ofdentin mineralization.

Metabolic, cellular, and developmental processes were the most affected biological functional annotations in both up‑ and down‑regulated transcripts. However, cell‑cell signaling, cell‑cell adhesion, cell cycle, induction of apoptosis, cell death, macrophage activation, ion transport, and responses to stress were the most affected subgroups of biological processes [Appendix Tables 1 and 2]. The competence of cells to sense and respond to their microenvironment is the basis

Figure 2: Diagram of the largest groups of downregulated biological processes in triethylene glycol dimethacrylate‑treated human dental pulp cells after (a) 1‑ and (b) 7‑day incubation period. The numbers designated in the pieces represent the number of genes those appear in any given category

b

a

Figure 3:Verification of themicroarray data using qRT‑PCRon thefollowing genes: (a) Bone morphogenetic protein‑2, bone morphogenetic protein‑4, secreted protein, acidic, cysteine‑rich, collagen type I alpha 1, interleukin‑6, oxidative stress‑induced growth inhibitor 1, (b) matrix metalloproteinase 3, and heme oxygenase‑1. Statistically significantdifferences are indicated by asterisks (P < 0.05)

b

a




of development, tissue repair, and immunity, as well as normal tissue homeostasis. These results reflect that thegenes showing the greatest changes in hDPCs exposed to TEGDMA were associated primarily with basic cellular activities, such as inflammation andwound healing, andthat TEGDMA causes changes in the coordination of cell actions. TEGDMA also caused some unusual systemic biological effects associated with fertilization and gamete generation. hDPCs are localized in an environment that is surrounded by hard dentin tissue, and nutritional support for hDPCs comes only through vessels in root canals. Thus, investigation of the release of unpolymerized dental resin monomers into the systemic circulation and possible effects on fertility is an important research topic.[14,15]

In addition, the results of the present study revealed important findings regarding the influence of TEGDMAon the mineralization of pulp cells. The genes most associated with pulp mineralization in this study were BMP-2, BMP-4, SPARC, and COL1A1. These genes encode ECM proteins and are used as markers of odontoblastic differentiation.[16‑18] TEGDMA exhibited both positive and negative regulation on the expression of mineralization‑related genes. While hDPCs showed an increase in BMP-2 expression after exposure to TEGDMA, BMP-4, SPARC, and COL1A1 were decreased in a time‑dependent manner. The results of the present study are consistent with a recent study that concluded that the dose of TEGDMA applied, and the influence of TEGDMA on the different intracellularsignaling pathways might affect the mineralization of pulp cells in different ways.[11] In addition, Galler et al. showed that TEGDMA caused dose‑ and time‑dependent decreases in the expression of genes associated with pulp mineralization, including collagen I, alkaline phosphatase, bone sialoprotein, osteocalcin, Runx2, and dentin sialophosphoprotein.[3] Moreover, our results provide insights into other mineralization‑related genes and have expanded the effects of TEGDMA on dentin mineralization.

Wound healing is a complex process in which hemostasis, inflammation,angiogenesis,ECMformation,remodeling by cell death, and apoptosis constitute some of the important stages in this process.[19] The results of the present study provide significant data regarding theeffects of TEGDMA on tissue repair. hDPCs exposed to TEGDMA showed up‑ and down‑regulation in genes mostly associated with responses to oxidative stress and inflammation. In addition, angiogenesis‑, bloodcoagulation‑, proliferation‑, and differentiation‑related genes were also identified, which changed significantlyover time [Appendix Tables 1 and 2]. OSGIN-1,

oxidative stress‑induced growth inhibitor 1, encodes an oxidative stress response protein and regulates apoptosis.[20] It also appears to be a key regulator of both inflammatory and anti‑inflammatorymolecules.HMOX1 plays a key role in the metabolism of heme and acts as a protective mechanism in the presence of oxidative stress.[21,22] In the present study, TEGDMA‑exposed hDPCs exhibited upregulated expression of the OSGIN-1 gene after 1‑ and 7‑day exposure periods compared with control group. However, TEGDMA caused a greater fold changeonlyafter1‑day incubationwhereasa significantexpression change after 7‑day incubation period was not detected. This might reflect the massive expressionof HMOX1 after the early exposure stage of hDPCs as an indicator of the initial protective effect of HMOX1 against TEGDMA‑induced reactive oxygen species, and other genes, such as OSGIN-1, continue to function as a part of the oxidative stress‑induced biological pathways. Previous studies have already shown initial HMOX1 expression in TEGDMA‑treated hDPCs.[11] However, OSGIN-1 and associated signaling pathways seem to be an attractive research area to examine the TEGDMA‑hDPCs interaction in terms of responses to oxidative stress.

Matrix metallopeptidase (MMP) are calcium‑ and zinc‑dependent endopeptidases that play roles in the remodeling and degradation of ECM.[23] However, the role of MMPs in wound healing is unclear. While Hiyama et al. reported that MMP-3 promotes and accelerates wound healing, Beidler et al. and Liu et al. reported that elevated MMP levels are associated with nonhealing.[24‑26] MMP-3 was upregulated after 1‑ and 7‑day exposure times in the present study. This suggests that MMP-3 may be involved in the wound healing process of pulp tissue treated with TEGDMA via reorganization of the ECM. However, further studies are needed to establish whether MMP-3 increases or reduces wound healing in TEGDMA‑treated hDPCs.

IL-6 acts as a pro‑ and anti‑inflammatory cytokine,and the release of this cytokine is important in the initiation of inflammatory processes after exposure toharmful foreign pathogens, such as viruses, bacteria, and chemicals.[13] Various studies have been carried out on different cell lines to show the effects of resin monomers on IL-6 secretion, and different results were obtained regarding the responses of the cells. A TEGDMA‑treated three‑dimensional human tissue model constructed from TR146 cells revealed an increase in the secretion of IL-6.[27] It has also been reported that costimulation of macrophages with lipopolysaccharides and TEGDMA resulted in a dose‑dependent decrease in the secretion of IL-6.[13] However, no significant changewas detected




in IL-6 production after the macrophages were treated with increasing concentrations of TEGDMA alone. In the present study, IL-6 expression in TEGDMA‑exposed hDPCs was inhibited after 1‑day incubation period. However, we did not detect a significant expressionchange after 7‑day incubation period. Although there are some contradictions, current and previous results described here reveal that TEGDMA has an important effect on inflammatory processes in terms of itsinhibition and/or stimulation. Experimental conditions and differences in the cell lines used may be a cause of the differences. However, the results presented herein suggest that TEGDMA inhibits the innate immune system in hDPCs by inhibiting the production of cytokines, including IL‑6. Disturbances of the innate immune system in the presence of TEGDMA may prevent hDPCs from generating a proper immune response and make the host vulnerable to pathogens.

Taken together, these findings revealed that variousbiological pathways contribute to the adverse effects of TEGDMA on hDPCs. Physical properties, such as low molecular weight and relatively high hydrophilicity, are the important factors for the penetration of TEGDMA to all biological compartments, and this may be the cause of different chemical‑biological interactions with intracellular processes.[28] The present study revealed that the vast majority of the differentially regulated transcripts play a role in DNA damage, oxidative stress, apoptosis, and negative regulation of dentin mineralization. Besides, TEGDMA revealed important changes in the inflammation and wound healingprocesses. Biocompatibility is defined as the absenceof inflammatory, irritating, toxic, or genotoxic effectsin biological systems and the aforementioned data revealed that TEGDMA does not have most of these biocompatibility features and cause multiple adverse effects on interacting cells. Consequently, it should be the aim of future studies to show the effects of TEGDMA in detail about interactions with intracellular processes and to develop more biocompatible monomers.

The small number of samples analyzed is a limitation of this study. However, the data provide new information about thegeneexpressionprofilesofhDPCs in responseto TEGDMA treatment.

ConclusionsWhile the detailed mechanism of toxicity is not completely understood, the present study revealed that TEGDMA can change the many functions of hDPCs through large changes in gene expression levels and complex interactions with different signaling pathways.

Financial support and sponsorshipThis study was supported by the Gulhane Military Medical Academy Research and Development Center, Ankara/Turkey (No: AR‑2012/11).

Conflicts of interestTherearenoconflictsofinterest.

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25. Hiyama T, Ozeki N, Mogi M, Yamaguchi H, Kawai R, Nakata K, et al. Matrix metalloproteinase‑3 in odontoblastic cells derived from ips cells: Unique proliferation response as odontoblastic cells derived from ES cells. PLoS One 2013;8:e83563.

26. Liu Y, Min D, Bolton T, Nubé V, Twigg SM, Yue DK, et al. Increased matrix metalloproteinase‑9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care 2009;32:117‑9.

27. Schmalz G, Schweikl H, Hiller KA. Release of prostaglandin E2, IL‑6 and IL‑8 from human oral epithelial culture models after exposure to compounds of dental materials. Eur J Oral Sci 2000;108:442‑8.

28. GeurtsenW.Biocompatibilityof resin‑modifiedfillingmaterials.Crit Rev Oral Biol Med 2000;11:333‑55.




App

endi

x Ta

ble

1: U

p-re

gula

ted

tran

scri

pts a

nd b

iolo

gica

l, on

tolo

gy-b

ased

ana

lyse

s in

trie

thyl

ene

glyc

ol d

imet

hacr

ylat

e-tr

eate

d de

ntal

pul

p ce

llsB

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Apo

ptot

ic

proc

ess

(GO

:000

6915

)

2521

4.4

4.4

Indu

ctio

n of

apo

ptos

is

(GO

:000

6917

)

CA

PN2,

FO

SL1,

L1C

AM

, LIF

, N

OVA

1, R

IPK

3, S

MO

X, T

NFR

SF10

A,

TNFR

SF10

D, T

NFR

SF1B

, TN

FRSF

21

CA

PN2,

FO

SL1,

IGF2

BP3

, LI

F, L

IMK

1, N

OVA

1, R

IPK

3,

TNFR

SF1B

, TN

FRSF

21

Indu

ctio

n of

apo

ptos

is

(GO

:000

6917

)11

9

Neg

ativ

e re

gula

tion

of

apop

totic

pro

cess

(G

O:0

0430

66)

DN

AJB

14, D

NA

JB9,

LIF

, MY

BL1

, SO

CS3

, TM

BIM

1, T

NFR

SF10

A,

TNFR

SF10

D, T

NFR

SF1B

, TN

FRSF

21

BIR

C3,

CD

163L

1, H

DA

C9,

LIF

, LO

XL4

, MY

BL1

, TN

FRSF

1B,

TNFR

SF21

Neg

ativ

e re

gula

tion

of a

popt

otic

pr

oces

s (G

O:0

0430

66)

108

Bio

logi

cal

adhe

sion

(G

O:0

0226

10)

3230

5.6

6.3

Cel

l adh

esio

n (G

O:0

0071

55)

AN

GPT

L4, A

TL1,

CD

151,

CD

46,

CD

55, C

D9,

CIT

, CLM

P, C

OL1

0A1,

C

TSL1

, CU

ZD1,

DC

BLD

2, D

NER

, F8

, ITG

A10

, ITG

A2,

ITG

A3,

ITG

A5,

IT

GA

6, L

1CA

M, L

AM

A5,

LA

MC

2,

MTS

S1, M

YPN

, NTN

4, N

TNG

1,

PGS1

, SG

IP1,

SM

AP2

, TSP

AN

12,

TSPA

N13

, VN

N1

AN

GPT

L4, A

TL1,

CD

163L

1,

CD

9, C

IT, C

LMP,

CO

L10A

1,

CO

L13A

1, C

OL4

A5,

CTS

L1,

DC

BLD

2, D

NER

, ITG

A10

, IT

GA

2, IT

GA

3, IT

GA

6,

LAM

A3,

LA

MA

5, L

AM

C2,

LO

XL4

, MTS

S1, M

YPN

, NTN

4,

PGS1

, RA

P1G

AP2

, SG

IP1,

SM

AP2

, TSP

AN

12, T

SPA

N13

, V

NN

1

Cel

l‑cel

l adh

esio

n (G

O:0

0163

37)

2018

Cel

l‑mat

rix a

dhes

ion

(GO

:000

7160

)6

6

Bio

logi

cal

regu

latio

n (G

O:0

0650

07)

8991

15.6

19.0

Hom

eost

atic

pr

oces

s (G

O:0

0425

92)

ATP2

A3,

ED

NR

B, G

PR39

, HK

2,

SOC

S3, S

TC1

ATP2

A3,

ATP

8B1,

CA

LB2,

C

OL1

3A1,

CO

L4A

5, E

DN

RB

, G

PR39

, HK

1, H

KD

C1,

STC

1

Cel

lula

r cal

cium

ion

hom

eost

asis

(G

O:0

0068

74)

24

Cel

lula

r glu

cose

hom

eost

asis

(G

O:0

0016

78)

32

Reg

ulat

ion

of li

quid

surf

ace

tens

ion

(GO

:005

0828

)

2

Reg

ulat

ion

of b

iolo

gica

l pr

oces

s (G

O:0

0507

89)

AD

RB

2, C

BX

7, C

LU, C

NO

T6L,

C

REM

, DN

AJB

14, D

NA

JB9,

DN

ER,

DU

SP10

, DU

SP6,

ED

NR

B, E

IF3G

, ET

S2, E

TV1,

FO

SL1,

HM

GA

1,

KLF

4, K

LF8,

LIF

, MA

FF, M

YB

L1,

NC

OA

3, N

R0B

1, N

R4A

2, N

RIP

3,

PDK

4, P

HF1

9, P

ITX

1, P

LAG

1,

PPA

RG

, PR

DM

8, P

SPC

1, R

FX8,

R

GS2

0, S

ALL

1, S

ERPI

NB

2,

SER

PIN

D1,

SER

PIN

E1, S

ERPI

NG

1,

SER

PIN

I1, S

FRP1

, SFR

P2, S

OC

S3,

STC

1, T

CF7

, TFA

P2A

, TFA

P2C

, TM

BIM

1, T

NFR

SF10

A, T

NFR

SF10

D,

TNFR

SF1B

, TN

FRSF

21, T

OX

2,

AD

RB

2, A

NK

RD

22, B

DK

RB

1,

BIR

C3,

CD

163L

1, C

LU, D

NER

, D

USP

6, E

DN

RB

, EFT

UD

1,

EIF4

A2,

ETS

2, E

TV1,

FO

SL1,

FZ

D8,

HD

AC

9, H

MG

A1,

H

MG

A2,

KC

NM

A1,

LIF

, LO

XL4

, MA

FF, M

EOX

1,

MY

BL1

, MY

C, N

CO

A3,

N

PAS3

, NR

0B1,

NR

5A2,

PA

X3,

PD

E12,

PD

K4,

PIT

X1,

PL

AG

1, P

OU

2F2,

PPA

RG

, R

FX8,

RG

S17,

RG

S20,

RG

S7,

SALL

1, S

ERPI

NB

2, S

ERPI

NB

8,

SER

PIN

E1, S

ERPI

NE2

,

Neg

ativ

e re

gula

tion

of a

popt

otic

pr

oces

s (G

O:0

0430

66)

108

Reg

ulat

ion

of c

ell c

ycle

(G

O:0

0517

26)

1

Reg

ulat

ion

of c

ellu

lar a

min

o ac

id m

etab

olic

pro

cess

(G

O:0

0065

21)

11

Reg

ulat

ion

of n

ucle

obas

e‑co

ntai

ning

com

poun

d m

etab

olic

pr

oces

s (G

O:0

0192

19)

3332

Reg

ulat

ion

of p

hosp

hate

m

etab

olic

pro

cess

(GO

:001

9220

)3

4

Regu

latio

n of

tran

slatio

n (G

O:0

0064

17)

23

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

TWIS

T2, W

NT1

6, W

NT5

B, Z

NF4

25,

ZNF4

51, Z

NF5

57SE

RPI

NI1

, SFR

P1, S

FRP2

, SM

UR

F2, S

OX

15, S

TC1,

TC

F7, T

FAP2

A, T

NFR

SF1B

, TN

FRSF

21, T

RIM

36, T

WIS

T2,

WN

T16,

WN

T5B

, ZN

F557

Reg

ulat

ion

of v

asoc

onst

rictio

n (G

O:0

0192

29)

23

Reg

ulat

ion

of m

olec

ular

fu

nctio

n (G

O:0

0650

09)

ARF

IP2,

ATL

1, B

CR, C

CNB1

, CC

ND

1, C

CND

3, C

DK

2AP2

, CST

1,

CST3

, CU

ZD1,

DCB

LD2,

DU

SP10

, EH

D1,

F8,

HPC

AL1

, LRR

C8C,

MLP

H,

NCA

LD, P

LCD

4, P

PP1R

1C, P

REX

1,

RGS2

0, R

IN1,

SEC

23B,

SER

PIN

B2,

SERP

IND

1, S

ERPI

NE1

, SER

PIN

G1,

SE

RPIN

I1, S

MA

P2, S

OCS

3,

TBC1

D15

, TBC

1D8,

TFP

I2, T

IMP4

AR

HG

AP2

0, A

TL1,

BC

R,

BIR

C3,

CC

ND

1, C

CN

E2,

CY

FIP2

, DC

BLD

2, E

HD

1,

GM

FG, H

PCA

L1, L

RR

C2,

M

LPH

, PR

EX1,

RA

P1G

AP2

, R

ASG

RP3

, RG

S17,

RG

S20,

R

GS7

, RIN

1, S

EC23

B,

SER

PIN

B2,

SER

PIN

B8,

SE

RPI

NE1

, SER

PIN

E2,

SER

PIN

I1, S

MA

P2, T

BC

1D8,

TF

PI, T

FPI2

, TR

IOB

P, Z

FR

Reg

ulat

ion

of c

atal

ytic

act

ivity

(G

O:0

0507

90)

3532

Cel

lula

r co

mpo

nent

or

gani

zatio

n or

bio

gene

sis

(GO

:007

1840

)

3828

6.7

5.8

Cel

lula

r co

mpo

nent

bi

ogen

esis

(G

O:0

0440

85)

HY

OU

1, Y

ME1

L1, H

SPA

5R

PS28

Prot

ein

com

plex

bio

gene

sis

(GO

:007

0271

)3

1

Cel

lula

r co

mpo

nent

or

gani

zatio

n (G

O:0

0160

43)

AR

FIP2

, CA

PG, C

BX

7, C

IT,

CO

L10A

1, C

OR

O2B

, FR

MD

4B,

GLD

N, H

IP1R

, HIS

T1H

1C,

HIS

T1H

2AB

, HIS

T1H

2AG

, H

IST1

H2B

C, H

IST1

H2B

J, H

IST1

H2B

K, H

IST2

H2A

A3,

INA

, K

IF18

A, K

IF21

A, K

IF3C

, KIF

C2,

M

LPH

, NPY

, RIP

K3,

SM

OX

, SM

TN,

SVIL

, TB

C1D

15, T

BC

1D8,

TO

X2,

TU

BG

2, W

HSC

1, Y

ME1

L1

AB

LIM

3, A

NK

1, C

IT,

CO

L10A

1, C

OL1

3A1,

CO

L4A

5,

CO

RO

2B, F

RM

D4B

, FZD

8,

GLD

N, H

CLS

1, H

DA

C9,

H

IST1

H1C

, HIS

T1H

2AB

, H

IST1

H2B

D, I

NA

, KRT

34,

LIM

K1,

MB

P, M

LPH

, NPY

, R

IPK

3, S

VIL

, TB

C1D

8,

TRIO

BP,

TU

BA

4A

Cel

lula

r com

pone

nt

mor

phog

enes

is (G

O:0

0329

89)

2220

Org

anel

le o

rgan

izat

ion

(GO

:000

6996

)14

6

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Cel

lula

r pr

oces

s (G

O:0

0099

87)

204

188

35.7

39.2

Cel

l cyc

le

(GO

:000

7049

)A

UR

KA

, CC

NB

1, C

CN

D1,

CC

ND

3,

CD

C20

, CD

K2A

P2, C

DK

N3,

CEL

F2,

CIT

, EFC

AB

2, E

MP1

, EM

P3,

EPG

N, E

REG

, ESP

L1, E

TS2,

ETV

1,

FGF1

3, F

OSL

1, H

MG

A1,

HS2

ST1,

K

IF18

A, K

IF20

A, K

IF21

A, K

IF3C

, K

IFC

2, L

1CA

M, M

AD

2L1,

MTS

S1,

MY

BL1

, NO

V, P

AR

D6B

, PG

F, P

OLM

, PR

KA

A2,

RIP

K3,

SD

AD

1, T

UB

G2,

V

EGFA

, VEG

FC, W

ISP2

CC

ND

1, C

CN

E2, C

DC

25A

, C

ELF2

, CIT

, EM

P1, E

PGN

, ER

EG, E

TS2,

ETV

1, F

AST

KD

2,

FGF1

3, F

OSL

1, H

DA

C9,

H

MG

A1,

HM

GA

2, H

S2ST

1,

LIM

K1,

MC

M3,

MC

M4,

M

PHO

SPH

6, M

TSS1

, MY

BL1

, M

YC

, NO

V, P

GF,

RA

SGR

P3,

RIP

K3,

SD

AD

1, S

GK

1,

TRIM

36, T

UB

A4A

, VEG

FC,

WIS

P2, Z

FR

Mei

osis

(GO

:000

7126

)7

1

Mito

sis (

GO

:000

7067

)15

8R

egul

atio

n of

cel

l cyc

le

(GO

:005

1726

)1

Cel

l co

mm

unic

atio

n (G

O:0

0071

54)

AD

RB

2, A

NG

PTL4

, ATL

1, B

CR

, B

MP2

, CA

CN

A1A

, CA

MK

2G,

CA

PN2,

CD

151,

CD

46, C

D55

, CD

9,

CD

97, C

DK

2AP2

, CIT

, CN

IH3,

C

RA

BP2

, CR

EM, C

UZD

1, C

XC

L11,

C

XC

L5, D

CB

LD2,

DEP

DC

1, D

NER

, D

USP

10, D

USP

6, E

DN

RB

, EFC

AB

2,

EHD

1, E

PGN

, ER

EG, E

TS2,

ETV

1,

F8, F

GF1

3, G

AB

BR

2, G

LDN

, G

PCPD

1, G

PR12

5, G

PR39

, GPR

56,

HM

13, H

PCA

L1, I

L13R

A2,

IL24

, IR

AK

2, IT

PR3,

L1C

AM

, LA

MA

5,

LAM

C2,

LIF

, LR

RC

8C, L

YPL

AL1

, M

EGF6

, NC

ALD

, NC

OA

3, N

OV,

N

OVA

1, N

PY, N

R4A

2, N

TN4,

N

TNG

1, P

AQ

R5,

PA

RD

6B, P

DK

4,

PGF,

PG

S1, P

LCD

4, P

PAPD

C1A

, PP

AR

G, P

PP1R

1C, P

RK

AA

2, P

RO

CR

, PT

CH

1, R

AC

2, R

HO

B, R

HO

U,

RIP

K3,

SC

N9A

, SEC

23B

, SEM

A3A

, SE

MA

4F, S

EMA

6D, S

FRP1

, SFR

P2,

SGIP

1, S

H2B

3, S

LC1A

1, S

LC22

A15

, SL

C22

A23

, SLC

22A

4, S

LC6A

15,

SMA

P2, S

OC

S3, S

PRY

2, S

PRY

4, S

RI,

STA

MB

PL1,

STC

1, S

TXB

P1,

AB

L2, A

DR

B2,

AN

GPT

L4,

AN

KR

D22

, AR

HG

AP2

0, A

TL1,

B

CR

, BD

KR

B1,

BM

P2, C

ALB

2,

CA

MK

2G, C

APN

2, C

CR

L1,

CD

163L

1, C

D9,

CIT

, CN

IH3,

C

OL1

3A1,

CO

L4A

5, C

SF2,

C

XC

L11,

CX

CL5

, CY

FIP2

, D

CB

LD2,

DN

ER, D

TX4,

D

USP

6, E

DN

RB

, EH

D1,

EPG

N,

EREG

, ETS

2, E

TV1,

F3,

FG

F13,

FG

F2, F

ZD8,

GA

BB

R2,

GLD

N,

GPR

39, G

PR56

, HPC

AL1

, IG

F2B

P3, I

L12A

, IL1

3RA

2,

IRA

K2,

ITPR

3, L

AM

A3,

LA

MA

5, L

AM

C2,

LIF

, LIM

K1,

LO

XL4

, LR

RC

2, L

YPL

AL1

, M

EGF6

, NC

OA

3, N

OV,

NO

VA1,

N

PY, N

RG

1, N

TN4,

PA

QR

5,

PDK

4, P

GF,

PG

S1, P

PAPD

C1A

, PP

AR

G, P

RO

CR

, PTC

HD

4,

RA

SGR

P3, R

IPK

3, S

CN

9A,

SEC

23B

, SEM

A4F

, SEM

A6D

, SF

RP1

, SFR

P2, S

GIP

1, S

GK

1,

SH2B

3, S

H2D

5, S

LC1A

1,

SLC

1A2,

SLC

22A

23, S

LC22

A4,

Cel

l‑cel

l sig

nalin

g (G

O:0

0072

67)

3329

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

SYT1

1, T

AC

R1,

TC

F7, T

NFR

SF10

A,

TNFR

SF10

D, T

NFR

SF1B

, TN

FRSF

21, T

OX

2, T

SPA

N12

, TS

PAN

13, V

EGFA

, VEG

FC, V

NN

1,

WIS

P2, W

NT1

6, W

NT5

B, Z

FAN

D5

SLC

6A15

, SLC

6A6,

SM

AP2

, SM

UR

F2, S

PRY

2, S

TAM

BPL

1,

STC

1, T

AC

R1,

TC

2N, T

CF7

, TN

FRSF

1B, T

NFR

SF21

, TR

IOB

P, T

SPA

N12

, TSP

AN

13,

VEG

FC, V

NN

1, W

ISP2

, W

NT1

6, W

NT5

BC

ellu

lar

com

pone

nt

mov

emen

t (G

O:0

0069

28)

AR

FIP2

, AD

RB

2, C

IT, D

NER

, EF

CA

B2,

EG

FL8,

FM

NL2

, ITP

R3,

LP

XN

, MTS

S1, N

OV,

NPY

, PX

N,

SMTN

, TU

BG

2, W

ISP2

AB

LIM

3, A

DR

B2,

CIT

, DN

ER,

EGFL

8, F

HO

D1,

ITPR

3, L

PXN

, M

TSS1

, NO

V, N

PY, P

XN

, SH

2D5,

TU

BA

4A, W

ISP2

Cel

lula

r com

pone

nt m

ovem

ent

(GO

:000

6928

)16

15

Chr

omos

ome

segr

egat

ion

(GO

:000

7059

)

HM

GA

1, K

IF18

A, K

IF20

A, K

IF21

A,

KIF

3C, K

IFC

2, M

AD

2L1,

TU

BG

2H

MG

A1,

HM

GA

2, T

UB

A4A

Chr

omos

ome

segr

egat

ion

(GO

:000

7059

)8

3

Cyt

okin

esis

(G

O:0

0009

10)

AU

RKA

, KIF

18A

, KIF

20A

, KIF

21A

, K

IF3C

, KIF

C2

Cyt

okin

esis

(GO

:000

0910

)6

Dev

elop

men

tal

proc

ess

(GO

:003

2502

)

107

9718

.720

.3A

nato

mic

al

stru

ctur

e m

orph

ogen

esis

(G

O:0

0096

53)

AR

FIP2

, CA

PG, C

IT, C

OL1

0A1,

D

USP

4, D

USP

5, D

USP

6, F

RM

D4B

, G

LDN

, HIP

1R, I

NA

, KIF

18A

, K

IF20

A, K

IF21

A, K

IF3C

, KIF

C2,

M

BP,

MLP

H, M

YPN

, NPY

, RIP

K3,

SM

TN, S

VIL

, TB

C1D

15, T

BC

1D8,

TU

BG

2

AB

LIM

3, A

NK

1, C

IT,

CO

L10A

1, C

OL1

3A1,

C

OL4

A5,

DU

SP4,

DU

SP5,

D

USP

6, F

RM

D4B

, FZD

8,

GLD

N, H

CLS

1, IN

A, K

RT34

, LI

MK

1, M

BP,

MLP

H, M

YPN

, N

PY, R

IPK

3, S

VIL

, TB

C1D

8,

TRIO

BP,

TU

BA

4A

Cel

lula

r com

pone

nt

mor

phog

enes

is (G

O:0

0329

89)

2220

Cel

l di

ffere

ntia

tion

(GO

:003

0154

)

DU

SP6,

TC

F7, W

NT1

6, W

NT5

BD

USP

6, F

ZD8,

TC

F7, W

NT1

6,

WN

T5B

Cel

l diff

eren

tiatio

n (G

O:0

0301

54)

45

Dea

th

(GO

:001

6265

)A

DA

M15

, AD

RB

2, C

APN

2, C

BX

7,

DN

AJB

14, D

NA

JB9,

DU

SP6,

FO

SL1,

H

GF,

HIP

1R, L

1CA

M, L

IF, M

YB

L1,

NO

VA1,

PLA

G1,

RIP

K3,

SM

OX

, SO

CS3

, TM

BIM

1, T

NFR

SF10

A,

TNFR

SF10

D, T

NFR

SF1B

, TN

FRSF

21, U

BE2

D1,

VAT

1L

AD

RB

2, A

NK

RD

22, B

IRC

3,

CA

PN2,

CD

163L

1, D

USP

6,

FOSL

1, H

DA

C9,

HG

F,

IGF2

BP3

, LIF

, LIM

K1,

LO

XL4

, M

YB

L1, N

OVA

1, P

LAG

1,

RIP

K3,

TN

FRSF

1B, T

NFR

SF21

, VA

T1L,

ZFR

Cel

l dea

th (G

O:0

0082

19)

2521

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Ecto

derm

de

velo

pmen

t (G

O:0

0073

98)

BM

P2, C

ELF2

, CR

AB

P2, C

REM

, C

UZD

1, D

CB

LD2,

DN

ER, E

DN

RB

, EM

P1, F

8, G

LDN

, L1C

AM

, LA

MA

5,

MA

ML3

, MTS

S1, N

R4A

2, N

TN4,

PI

TX1,

SEM

A3A

, SEM

A4F

, SE

MA

6D, S

GIP

1, T

FAP2

A, T

FAP2

C,

TNFR

SF10

A, T

NFR

SF10

D,

TNFR

SF1B

, TN

FRSF

21

AB

LIM

3, B

MP2

, CEL

F2,

CO

L13A

1, C

OL4

A5,

DC

BLD

2,

DN

ER, E

DN

RB

, EM

P1,

GLD

N, G

MFG

, LA

MA

3,

LAM

A5,

MTS

S1, N

PAS3

, N

RG

1, N

TN4,

PA

X3,

PIT

X1,

SE

MA

4F, S

EMA

6D, S

GIP

1,

SH2D

5, T

FAP2

A, T

NFR

SF1B

, TN

FRSF

21

Ecto

derm

dev

elop

men

t (G

O:0

0073

98)

2826

Embr

yo

deve

lopm

ent

(GO

:000

9790

)

CIT

, DU

SP4,

DU

SP5,

DU

SP6

CIT

, CPE

B2,

DU

SP4,

DU

SP5,

D

USP

6, L

IMK

1Em

bryo

dev

elop

men

t (G

O:0

0097

90)

46

Endo

derm

de

velo

pmen

t (G

O:0

0074

92)

DU

SP4,

DU

SP5,

DU

SP6

DU

SP4,

DU

SP5,

DU

SP6

Endo

derm

dev

elop

men

t (G

O:0

0074

92)

33

Mes

oder

m

deve

lopm

ent

(GO

:000

7498

)

AD

AM

15, B

MP2

, CD

97, C

OL1

0A1,

C

UZD

1, D

CB

LD2,

ETS

2, E

TV1,

F8

, FG

F13,

GPR

125,

GPR

56, K

LF4,

K

LF8,

L1C

AM

, LPX

N, M

YPN

, NO

V,

PBX

1, P

GS1

, PIT

X1,

PR

KA

A2,

PT

HLH

, PX

N, S

EMA

3A, S

EMA

4F,

SEM

A6D

, SO

CS3

, SPR

Y2,

SPR

Y4,

SP

RY4,

TN

FRSF

1B, T

WIS

T2, W

ISP2

BM

P2, C

DH

6, C

OL1

0A1,

C

OL1

3A1,

CO

L4A

5, D

CB

LD2,

ET

S2, E

TV1,

FG

F13,

GPR

56,

LPX

N, M

EOX

1, M

YPN

, NO

V,

PAX

3, P

BX

1, P

CD

H9,

PG

S1,

PITX

1, P

THLH

, PX

N, S

EMA

4F,

SEM

A6D

, SH

2D5,

SPR

Y2,

SP

RYD

4, T

NFR

SF1B

, TW

IST2

, W

ISP2

Mes

oder

m d

evel

opm

ent

(GO

:000

7498

)34

29

Patte

rn

specification

proc

ess

(GO

:000

7389

)

DU

SP6,

KLF

8, P

ITX

1D

USP

6, P

AX

3, P

ITX

1, Z

FRA

nter

ior/p

oste

rior a

xis

specification(GO:0009948)

11

Segm

entspecification

(GO

:000

7379

)1

2

Sex

dete

rmin

atio

n (G

O:0

0075

30)

NR

0B1

NR

0B1

Sex

dete

rmin

atio

n (G

O:0

0075

30)

11

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Syst

em

deve

lopm

ent

(GO

:004

8731

)

AD

AM

15, A

NG

PTL4

, BM

P2,

CA

MK

2G, C

D97

, CEL

F2, C

OL1

0A1,

C

REM

, CU

ZD1,

CX

CL1

1, C

XC

L5,

DC

BLD

2, D

USP

6, E

DN

RB

, ETS

2,

ETV

1, F

8, F

GF1

3, G

LDN

, GPR

125,

G

PR56

, IL1

3RA

2, K

LF4,

KLF

8,

L1C

AM

, LA

MA

5, L

PXN

, MA

ML3

, M

TSS1

, MY

PN, N

OV,

NTN

4,

NTN

G1,

PB

X1,

PG

F, P

GS1

, PIT

X1,

PR

KA

A2,

PTH

LH, P

XN

, SEM

A3A

, SE

MA

4F, S

EMA

6D, S

FRP1

, SF

RP2

, SG

IP1,

SO

CS3

, SPR

Y4,

TC

F7, T

NFR

SF10

A, T

NFR

SF10

D,

TNFR

SF1B

, TN

FRSF

21, T

WIS

T2,

VEG

FA, V

EGFC

, WIS

P2, W

NT1

6,

WN

T5B

AB

LIM

3, A

NG

PTL4

, BM

P2,

CA

MK

2G, C

DH

6, C

ELF2

, C

OL1

0A1,

CX

CL1

1, C

XC

L5,

DC

BLD

2, D

USP

6, E

DN

RB

, ET

S2, E

TV1,

FG

F13,

FZD

8,

GLD

N, G

MFG

, GPR

56,

IL13

RA

2, L

AM

A3,

LA

MA

5,

LPX

N, M

EOX

1, M

TSS1

, M

YPN

, NG

F, N

OV,

NPA

S3,

NR

G1,

NTN

4, P

AX

3, P

BX

1,

PCD

H9,

PG

F, P

GS1

, PIT

X1,

PT

HLH

, PX

N, S

EMA

4F,

SEM

A6D

, SFR

P1, S

FRP2

, SG

IP1,

SH

2D5,

SPR

YD

4,

TCF7

, TN

FRSF

1B, T

NFR

SF21

, TW

IST2

, VEG

FC, W

ISP2

, W

NT1

6, W

NT5

B

Ang

ioge

nesi

s (G

O:0

0015

25)

1812

Hea

rt de

velo

pmen

t (G

O:0

0075

07)

139

Hem

opoi

esis

(GO

:003

0097

)5

4M

uscl

e or

gan

deve

lopm

ent

(GO

:000

7517

)4

7

Ner

vous

syst

em d

evel

opm

ent

(GO

:000

7399

)30

32

Skel

etal

syst

em d

evel

opm

ent

(GO

:000

1501

)9

9

Gro

wth

(G

O:0

0400

07)

11

0.2

0.2

Gro

wth

(G

O:0

0400

07)

DU

SP6

DU

SP6

Gro

wth

(GO

:004

0007

)1

1

Imm

une

syst

em

proc

ess

(GO

:000

2376

)

7364

12.8

13.4

Ant

igen

pr

oces

sing

and

pr

esen

tatio

n (G

O:0

0198

82)

CTS

S, M

ICA

, RA

ET1G

Ant

igen

pro

cess

ing

and

pres

enta

tion

of p

eptid

e or

po

lysa

ccha

ride

antig

en v

ia M

HC

cl

ass I

I (G

O:0

0025

04)

1

Imm

une

resp

onse

(G

O:0

0069

55)

AD

RB

2, A

TL1,

CC

L26,

CC

L5, C

D55

, C

D97

, CLE

C2B

, CO

L10A

1, C

XC

L11,

C

XC

L5, E

TS2,

ETV

1, G

PR12

5,

GPR

56, I

L13R

A2,

IL24

, KLF

4, K

LF8,

M

ASP

1, M

ICA

, NPT

X1,

PO

LM,

RA

ET1G

, SH

2B3,

TN

FRSF

10A

, TN

FRSF

10D

, TN

FRSF

1B, T

NFR

SF21

AD

RB

2, A

TL1,

CC

L5, C

CR

L1,

CLE

C2B

, CO

L10A

1, C

SF2,

C

XC

L11,

CX

CL5

, ETS

2, E

TV1,

F3

, GPR

56, I

L12A

, IL1

3RA

2,

NPT

X1,

SH

2B3,

TN

FRSF

1B,

TNFR

SF21

, ZFR

B c

ell‑m

edia

ted

imm

unity

(G

O:0

0197

24)

147

Com

plem

ent a

ctiv

atio

n (G

O:0

0069

56)

31

Nat

ural

kill

er c

ell a

ctiv

atio

n (G

O:0

0301

01)

13

Res

pons

e to

inte

rfer

on‑g

amm

a (G

O:0

0343

41)

13

Mac

roph

age

activ

atio

n (G

O:0

0421

16)

AD

RB

2, A

TL1,

CD

97, C

OLE

C12

, C

XC

L11,

CX

CL5

, ETS

2, E

TV1,

IL24

, SC

AR

A5,

TN

FRSF

10A

, TN

FRSF

10D

, TN

FRSF

1B, T

NFR

SF21

AD

RB

2, A

TL1,

CD

163L

1,

CO

L4A

5, C

OLE

C12

, CX

CL1

1,

CX

CL5

, ETS

2, E

TV1,

F3,

IL

12A

, LO

XL4

, SC

AR

A5,

TN

FRSF

1B, T

NFR

SF21

Mac

roph

age

activ

atio

n (G

O:0

0421

16)

1415

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Loca

lizat

ion

(GO

:005

1179

)90

6815

.814

.2Pr

otei

n lo

caliz

atio

n (G

O:0

0081

04)

PAR

D6B

, STX

1AST

X1A

Asy

mm

etric

pro

tein

loca

lizat

ion

(GO

:000

8105

)1

1

RN

A lo

caliz

atio

n (G

O:0

0064

03)

CFE

B1

CPE

B2,

RPS

28, Z

FRR

NA

loca

lizat

ion

(GO

:000

6403

)1

3

Tran

spor

t (G

O:0

0068

10)

AB

CA

3, A

BC

A6,

AB

CG

2, A

CSL

4,

AD

RB

2, A

KR

1B1,

AK

R1C

1, A

LG10

, A

P2M

1, A

TP2A

3, A

TP6V

0B,

ATP6

V0C

, ATP

6V0E

2, A

TP6V

1G2‑

DD

X39

B, B

ET1,

CA

CN

A1A

, CD

46,

CD

55, C

D68

, CD

97, C

LCA

2, C

LGN

, C

NIH

3, C

OLE

C12

, CR

AB

P2, C

UZD

1,

DC

BLD

2, E

HD

1, E

RO

1LB

, F8,

FX

YD

5, G

LDN

, GPR

125,

GPR

56,

ITPR

3, K

CN

N4,

KIF

18A

, KIF

20A

, K

IF21

A, K

IF3C

, KIF

C2,

MFS

D8,

M

LPH

, NO

VA1,

NR

IP3,

PIT

PNC

1,

PKD

1P1,

PPI

F, P

REB

, PTC

H1,

RA

C2,

R

HO

B, R

HO

U, R

IN1,

SC

AR

A5,

SC

N9A

, SEC

23B

, SLC

12A

7,

SLC

16A

14, S

LC16

A4,

SLC

16A

6,

SLC

1A1,

SLC

20A

1, S

LC22

A15

, SL

C22

A23

, SLC

22A

4, S

LC31

A2,

SL

C35

B1,

SLC

35E4

, SLC

35G

2,

SLC

37A

2, S

LC47

A1,

SLC

6A15

, SL

CO

4A1,

SN

CA

, SO

CS3

, STX

1A,

STX

BP1

, SY

T11,

SY

T7, T

BC

1D15

, TB

C1D

8, T

MED

5, T

RPV

2, T

UB

G2,

U

CP2

, XPO

1, Y

ME1

L1

AB

CA

6, A

BC

A8,

AB

CD

3,

AB

CG

2, A

CSL

4, A

DR

B2,

A

KR

1B1,

AK

R1B

10, A

KR

1B15

, A

KR

1C1,

AN

KR

D22

, ATP

2A3,

AT

P8B

1, C

D16

3L1,

CD

68,

CLC

A2,

CLG

N, C

NIH

3,

CO

L13A

1, C

OL4

A5,

CO

LEC

12,

DC

BLD

2, D

NA

JC6,

EH

D1,

G

LDN

, GPR

56, I

GF2

BP3

, IT

PR3,

KC

NM

A1,

KC

NN

4,

LOX

L4, M

CO

LN3,

MLP

H,

NO

VA1,

OSB

PL3,

PPI

F,

PTC

HD

4, R

IN1,

RPS

28,

SCA

MP3

, SC

AR

A5,

SC

FD2,

SC

N9A

, SEC

23B

, SLC

12A

7,

SLC

16A

2, S

LC16

A6,

SLC

17A

5,

SLC

1A1,

SLC

1A2,

SLC

20A

1,

SLC

22A

23, S

LC22

A4,

SL

C47

A1,

SLC

6A15

, SLC

6A6,

SL

C7A

14, S

LCO

2B1,

SL

CO

4A1,

SN

CA

, STX

1A,

TBC

1D8,

TC

2N, T

PCN

1,

TRPV

2, T

UB

A4A

, ZFR

Am

ino

acid

tran

spor

t (G

O:0

0068

65)

35

carb

ohyd

rate

tran

spor

t (G

O:0

0086

43)

63

Extra

cellu

lar t

rans

port

(GO

:000

6858

)5

7

ion

trans

port

(GO

:000

6811

)26

22Li

pid

trans

port

(GO

:000

6869

)13

9Ly

soso

mal

tran

spor

t (G

O:0

0070

41)

33

mito

chon

dria

l tra

nspo

rt (G

O:0

0068

39)

1

Nuc

lear

tran

spor

t (G

O:0

0511

69)

34

nucl

eoba

se‑c

onta

inin

g co

mpo

und

trans

port

(GO

:001

5931

)

32

Met

abol

ic

proc

ess

(GO

:000

8152

)

271

226

47.5

47.2

Bio

synt

hetic

pr

oces

s (G

O:0

0090

58)

PLA

G1,

TC

F7PL

AG

1, T

CF7

Bio

synt

hetic

pro

cess

(G

O:0

0090

58)

22

Cat

abol

ic p

roce

ss

(GO

:000

9056

) H

AC

E1, H

K2,

GLA

, NED

D4L

, R

GS2

0G

LA, H

ERC

5, H

K1,

HK

DC

1,

RG

S17,

RG

S20,

RG

S7,

SMU

RF2

Cat

abol

ic p

roce

ss (G

O:0

0090

56)

58

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Coe

nzym

e m

etab

olic

pr

oces

s (G

O:0

0067

32)

AC

AD

VL,

AU

H, D

LST,

MTH

FSD

Acy

l‑CoA

met

abol

ic p

roce

ss

(GO

:000

6637

) 1

Gen

erat

ion

of p

recu

rsor

m

etab

olite

s an

d en

ergy

(G

O:0

0060

91)

AC

AD

VL,

AD

CK

2, C

OX

7A2,

C

YP1

9A1,

CY

P26B

1, E

RO

1LB

, HK

2,

ND

UFS

2, S

MO

X, U

GD

H, X

DH

, ZF

AN

D5

CO

X7A

2, C

YP2

6B1,

HK

1,

HK

DC

1, M

DH

2, N

DU

FS2,

TX

NR

D1,

UG

DH

, XD

H

Oxi

dativ

e ph

osph

oryl

atio

n (G

O:0

0061

19)

32

Res

pira

tory

ele

ctro

n tra

nspo

rt ch

ain

(GO

:002

2904

)11

6

Nitr

ogen

co

mpo

und

met

abol

ic

proc

ess

(GO

:000

6807

)

AC

AD

VL,

GLA

, GLU

L, H

MO

X1,

PL

AG

1, R

GS2

0, S

MO

X, T

CF7

GLA

, PLA

G1,

RG

S17,

RG

S20,

R

GS7

, TC

F7, T

XN

RD

1Po

rphy

rin‑c

onta

inin

g co

mpo

und

met

abol

ic p

roce

ss (G

O:0

0067

78)

2

Phos

phat

e‑co

ntai

ning

co

mpo

und

met

abol

ic

proc

ess

(GO

:000

6796

)

AB

CA

3, A

BC

A6,

AC

YP1

, DU

SP10

, D

USP

4, D

USP

5, D

USP

6, G

LDN

, H

K2,

MG

LL, N

EK2,

NU

DT7

, PB

K,

PLC

D4,

PPA

PDC

1A, R

GS2

0, R

IPK

3,

SLC

20A

1, S

LC22

A15

, SLC

22A

23,

SLC

22A

4, S

LC37

A2,

STC

1, U

CP2

AB

CA

6, A

BC

A8,

AC

YP1

, A

NK

RD

22, C

DC

25A

, DU

SP4,

D

USP

5, D

USP

6, G

LDN

, HK

1,

HK

DC

1, L

IMK

1, P

LA2G

15,

PPA

PDC

1A, R

GS1

7, R

GS2

0,

RG

S7, R

IPK

3, S

LC17

A5,

SL

C20

A1,

SLC

22A

23,

SLC

22A

4, S

TC1

Phos

phol

ipid

met

abol

ic p

roce

ss

(GO

:000

6644

)5

5

Reg

ulat

ion

of p

hosp

hate

m

etab

olic

pro

cess

(GO

:001

9220

)3

4

Prim

ary

met

abol

ic

proc

ess

(GO

:004

4238

)

AB

CA

3, A

BC

A6,

AB

CG

2, A

BH

D14

A‑

AC

Y1,

AB

HD

6, A

CA

DV

L, A

CSL

4,

AD

RB

2, A

K2,

AK

4, A

MD

HD

1,

AM

PD3,

AN

PEP,

AN

XA

11,

APO

BEC

3B, A

TL1,

ATP

6V1G

2‑D

DX

39B

, AU

H, A

UR

KA

, BTB

D11

, C

AM

K2G

, CA

PN2,

CB

X7,

CD

46,

CD

55, C

D68

, CD

C20

, CD

K2A

P2,

CD

KN

3, C

DO

1, C

ELF2

, CH

ST2,

CIT

, C

LGN

, CLP

TM1,

CLU

, CN

OT6

L,

CPE

B1,

CPX

M2,

CR

AB

P2, C

REM

, C

ST1,

CST

3, C

STF3

, CTB

S, C

TSF,

C

TSL1

, CTS

S, C

UZD

1, C

XX

C1,

C

YP1

9A1,

DC

BLD

2, D

LST,

DN

AJA

3,

DN

AJB

14, D

NA

JB9,

DN

ER, D

PP4,

AB

CA

6, A

BC

A8,

AB

CD

3,

AB

CG

2, A

BL2

, AC

SL4,

AD

RB

2,

ALD

H3A

1, A

MD

HD

1, A

MPD

3,

AN

KR

D22

, AN

PEP,

AN

XA

11,

ATL1

, ATP

8B1,

B3G

AT3,

B

TBD

11, B

TBD

3, C

AM

K2G

, C

AM

KK

1, C

APN

2, C

D16

3L1,

C

D68

, CD

C25

A, C

DO

1, C

ELF2

, C

HST

2, C

IT, C

LGN

, CLU

, C

PA4,

CPE

B2,

CST

F3, C

TBS,

C

TSL1

, DC

AF1

3, D

CB

LD2,

D

ENN

D3,

DN

AJC

6, D

NER

, D

PP4,

DTX

4, D

USP

4, D

USP

5,

DU

SP6,

ED

EM2,

ED

NR

B,

EFTU

D1,

EIF

4A2,

EN

PP2,

carb

ohyd

rate

met

abol

ic p

roce

ss

(GO

:000

5975

)30

26

Cel

lula

r am

ino

acid

met

abol

ic

proc

ess (

GO

:000

6520

)15

12

Lipi

d m

etab

olic

pro

cess

(G

O:0

0066

29)

2522

Nuc

leob

ase‑

cont

aini

ng

com

poun

d m

etab

olic

pro

cess

(G

O:0

0061

39)

7264

prot

ein

met

abol

ic p

roce

ss

(GO

:001

9538

)92

79

Cont

d...




Cont

d...

App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

DU

SP10

, DU

SP4,

DU

SP5,

DU

SP6,

ED

NR

B, E

IF3G

, EN

PP2,

EN

PP4,

EN

TPD

1, E

RO

1LB

, ETS

2, E

TV1,

F8

, FK

BP1

A, F

OSL

1, G

ALE

, G

ALN

T12,

GA

LNT6

, GB

A, G

GT1

, G

K, G

LA, G

LB1L

, GLU

L, G

PR39

, G

PR89

A, G

PX3,

HA

CE1

, HA

S3,

HIP

K2,

HIS

T1H

1C, H

IST1

H2A

B,

HIS

T1H

2AG

, HIS

T1H

2BC

, H

IST1

H2B

D, H

IST1

H2B

J, H

IST1

H2B

K, H

IST2

H2A

A3,

HK

2,

HM

GA

1, H

S2ST

1, H

SD3B

7, H

SPA

5,

HSP

B8,

HY

OU

1, IR

AK

2, K

LF4,

K

LF8,

KY

NU

, L1C

AM

, LR

RC

8C,

LYPL

AL1

, MA

FF, M

AR

S2, M

ASP

1,

MFS

D8,

MG

LL, M

MP1

0, M

MP3

, M

YB

L1, M

YPN

, NC

OA

3, N

EDD

4L,

NEK

2, N

OVA

1, N

R0B

1, N

R4A

2,

NR

IP3,

NT5

E, O

DC

1, P

AM

R1,

PA

QR

5, P

BK

, PB

X1,

PD

K4,

PH

F19,

PI

GF,

PIG

W, P

ITPN

C1,

PIT

X1,

PL

AG

1, P

LAT,

PLA

U, P

LCD

4, P

NP,

PO

LM, P

PAPD

C1A

, PPA

RG

, PPI

F,

PRD

M8,

PR

EB, P

RK

AA

2, P

SPC

1,

PTC

H1,

PTP

N3,

PY

GB

, QPC

T, R

FX8,

R

GS2

0, R

IPK

3, R

NF1

57, R

PP25

, SA

LL1,

SD

F2L1

, SEL

T, S

ERPI

NB

2,

SER

PIN

D1,

SER

PIN

E1, S

ERPI

NG

1,

SER

PIN

I1, S

GIP

1, S

LC1A

1,

SLC

22A

15, S

LC22

A23

, SLC

22A

4,

SLC

35B

1, S

LC35

E4, S

LC37

A2,

SL

C3A

2, S

LC6A

15, S

MO

X, S

PRY

4,

SRI,

SRSF

5, S

YV

N1,

TC

F7, T

FAP2

A,

TFA

P2C

, TFP

I2, T

IMP4

, TM

X3,

TO

R4A

, TO

X2,

TW

IST2

, UB

E2D

1,

UC

P2, U

GD

H, U

GG

T2, U

PP1,

USP

36,

VAT1

L, W

HSC

1, X

DH

, XPO

1,

YM

E1L1

, ZN

F425

, ZN

F451

, ZN

F557

ENPP

4, E

RMP1

, ETS

2, E

TV1,

FD

XA

CB1,

FK

BP1A

, FO

SL1,

G

6PD

, GA

LE, G

ALN

T12,

GB

A,

GCN

T3, G

LA, G

LB1L

, GM

2A,

GPR

39, H

AD

H, H

AS3

, HC

LS1,

H

DA

C9, H

ERC5

, HIP

K2,

H

IST1

H1C

, HIS

T1H

2AB

, H

IST1

H2B

D, H

K1,

HK

DC

1,

HM

GA

1, H

MG

A2,

HS2

ST1,

H

SD3B

7, H

SPB8

, IG

F2B

P3,

IRA

K2,

KY

NU

, LIM

K1,

LO

XL4

, LR

RC2,

LY

PLA

L1, M

AFF

, M

ARS

2, M

CM3,

MCM

4, M

DH

2,

MEO

X1,

MM

P10,

MM

P3,

MY

BL1,

MY

C, M

YPN

, NC

OA

3,

NO

VA1,

NPA

S3, N

PM1,

NR

0B1,

N

R5A

2, N

T5E,

OSB

PL3,

PA

MR1

, PA

QR5

, PA

X3,

PB

X1,

PD

E12,

PD

K4,

PIG

W, P

ITX

1,

PLA

2G15

, PLA

G1,

PLA

T, P

LAU

, PN

P, P

OU

2F2,

PPA

PDC

1A,

PPA

RG, P

PIF,

PSM

C2, P

TCH

D4,

PT

PN3,

QPC

T, R

FX8,

RG

S17,

RG

S20,

RG

S7, R

IPK

3, R

NF1

57,

RPP2

5, S

ALL

1, S

ERPI

NB

2,

SERP

INB8

, SER

PIN

E1,

SERP

INE2

, SER

PIN

I1, S

F3B

3,

SGIP

1, S

GK

1, S

LC17

A5,

SL

C1A

1, S

LC1A

2, S

LC22

A23

, SL

C22A

4, S

LC6A

15, S

LC6A

6,

SLC7

A14

, SM

URF

2, S

OX

15,

SPRY

D4,

SQ

STM

1, S

TIP1

, TC

F7, T

FAP2

A, T

FPI,

TFPI

2,

TIPA

RP, T

MX

4, T

OR4

A,

TRIM

36, T

WIS

T2, T

XN

RD

1,

TYSN

D1,

UG

DH

, UG

GT2

, U

SP53

, VAT

1L, W

HSC

1, X

DH

, ZB

TB21

, ZFR

, ZN

F557

Tric

arbo

xylic

aci

d cy

cle

(GO

:000

6099

)1




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Sulfu

r com

poun

d m

etab

olic

pr

oces

s (G

O:0

0067

90)

HS2

ST1

HS2

ST1

Sulfu

r com

poun

d m

etab

olic

pr

oces

s (G

O:0

0067

90)

11

Vita

min

m

etab

olic

pr

oces

s (G

O:0

0067

66)

AU

H, G

GH

, VN

N1

VN

N1

Vita

min

bio

synt

hetic

pro

cess

(G

O:0

0091

10)

11

Mul

ticel

lula

r or

gani

smal

pr

oces

s (G

O:0

0325

01)

5654

9.8

11.3

Sing

le‑

mul

ticel

lula

r or

gani

sm p

roce

ss

(GO

:004

4707

)

AD

AM

15, A

DR

B2,

CA

CN

A1A

, C

D15

1, C

D9,

CD

97, C

ELF2

, CR

EM,

CU

ZD1,

DC

BLD

2, D

USP

4, D

USP

5,

DU

SP6,

ED

NR

B, E

HD

1, F

8, F

OSL

1,

GA

BB

R2,

GPR

125,

GPR

39, G

PR56

, H

PCA

L1, H

SPB

8, IT

PR3,

KLF

8,

L1C

AM

, LA

MA

5, L

IF, M

YPN

, N

CA

LD, N

OVA

1, N

TN4,

PIT

PNC

1,

PITX

1, P

RK

AA

2, S

CN

9A, S

EMA

3A,

SEM

A4F

, SEM

A6D

, SFR

P1, S

FRP2

, SL

C1A

1, S

LC22

A15

, SLC

22A

23,

SLC

22A

4, S

LC6A

15, S

TXB

P1,

SYT1

1, T

AC

R1,

TC

F7, T

OR

4A,

TRPV

2, T

SPA

N12

, WN

T16,

WN

T5B

, ZF

AN

D5

AD

RB

2, A

TXN

7L1,

BD

KR

B1,

C

CR

L1, C

D9,

CD

H6,

CEL

F2,

CO

L13A

1, C

OL4

A5,

DC

BLD

2,

DU

SP4,

DU

SP5,

DU

SP6,

ED

NR

B, E

HD

1, F

OSL

1, F

ZD8,

G

AB

BR

2, G

PR39

, GPR

56,

HPC

AL1

, HSP

B8,

IGF2

BP3

, IT

PR3,

LA

MA

3, L

AM

A5,

LI

F, L

OX

L4, M

YPN

, NO

VA1,

N

TN4,

PA

X3,

PC

DH

9, P

ITX

1,

SCN

9A, S

EMA

4F, S

EMA

6D,

SFR

P1, S

FRP2

, SLC

1A1,

SL

C1A

2, S

LC22

A23

, SLC

22A

4,

SLC

6A15

, SLC

6A6,

TA

CR

1,

TC2N

, TC

F7, T

OR

4A, T

RPV

2,

TSPA

N12

, WN

T16,

WN

T5B

, ZF

R

Patternsp

ecificationprocess

(GO

:000

7389

)3

4

Syst

em p

roce

ss (G

O:0

0030

08)

4643

Rep

rodu

ctio

n (G

O:0

0000

03)

2013

3.5

2.7

Ferti

lizat

ion

(GO

:000

9566

)A

DA

M15

Fe

rtiliz

atio

n (G

O:0

0095

66)

1

Gam

ete

gene

ratio

n (G

O:0

0072

76)

BM

P2, C

CN

B1,

CC

ND

1, C

CN

D3,

C

D15

1, C

D9,

CD

97, D

NA

JB14

, D

NA

JB9,

GPR

125,

GPR

56, P

RK

AA

2,

PSPC

1, R

IPK

3, T

SPA

N12

, TSP

AN

13,

USP

36

BM

P2, C

CN

D1,

CC

NE2

, C

D9,

GPR

56, L

IMK

1, R

IPK

3,

TSPA

N12

, TSP

AN

13, Z

FR

Fem

ale

gam

ete

gene

ratio

n (G

O:0

0072

92)

23

Sper

mat

ogen

esis

(GO

:000

7283

)10

4

Res

pons

e to

stim

ulus

(G

O:0

0508

96)

8581

15.5

17.7

Cel

lula

r def

ense

re

spon

se

(GO

:000

6968

)

CX

CL1

1, C

XC

L5, E

TS2,

ETV

1,

MIC

A, P

OLM

, RA

ET1G

, SH

2B3,

SP

RY4,

TN

FRSF

10A

, TN

FRSF

10D

, TN

FRSF

1B, T

NFR

SF21

AR

HG

AP2

0, C

D16

3L1,

C

XC

L11,

CX

CL5

, ETS

2, E

TV1,

F3

, IL1

2A, L

OX

L4, S

H2B

3,

SH2D

5, S

PRY

D4,

SQ

STM

1,

TNFR

SF1B

, TN

FRSF

21

Cel

lula

r def

ense

resp

onse

(G

O:0

0069

68)

1315

Cont

d...




App

endi

x Ta

ble

1: C

ontd

...B

iolo

gica

l pr

oces

s (up

-re

gula

ted)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l (%

)

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bio

logi

cal

proc

ess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Def

ense

resp

onse

to

bac

teriu

m

(GO

:004

2742

)

CO

LEC

12, S

CA

RA

5C

OLE

C12

, SC

AR

A5

Def

ense

resp

onse

to b

acte

rium

(G

O:0

0427

42)

22

İmmuneresponse

(GO

:000

6955

)A

DR

B2,

ATL

1, C

CL2

6, C

CL5

, CD

55,

CD

97, C

LEC

2B, C

OL1

0A1,

CX

CL1

1,

CX

CL5

, ETS

2, E

TV1,

GPR

125,

G

PR56

, IL1

3RA

2, IL

24, K

LF4,

KLF

8,

MA

SP1,

MIC

A, N

PTX

1, P

OLM

, R

AET

1G, S

H2B

3, T

NFR

SF10

A,

TNFR

SF10

D, T

NFR

SF1B

, TN

FRSF

21

AD

RB

2, A

TL1,

CC

L5, C

CR

L1,

CLE

C2B

, CO

L10A

1, C

SF2,

C

XC

L11,

CX

CL5

, ETS

2, E

TV1,

F3

, GPR

56, I

L12A

, IL1

3RA

2,

NPT

X1,

SH

2B3,

TN

FRSF

1B,

TNFR

SF21

, ZFR

B c

ell‑

med

iate

d im

mun

ity

(GO

:001

9724

)14

7

Com

plem

ent a

ctiv

atio

n (G

O:0

0069

56)

31

Nat

ural

kill

er c

ell a

ctiv

atio

n (G

O:0

0301

01)

13

Res

pons

e to

inte

rfer

on‑g

amm

a (G

O:0

0343

41)

13

Res

pons

e to

en

doge

nous

st

imul

us

(GO

:000

9719

)

DU

SP6

DU

SP6,

SM

UR

F2R

espo

nse

to e

ndog

enou

s st

imul

us (G

O:0

0097

19)

12

Res

pons

e to

ex

tern

al st

imul

us

(GO

:000

9605

)

CD

151,

CD

46, C

D55

, CD

9, C

UZD

1,

CX

CL5

, DC

BLD

2, F

8, P

AM

R1,

PLA

T,

PRO

CR

, TFP

I2, T

SPA

N12

, TSP

AN

13

CD

9, C

XC

L5, D

CB

LD2,

F3,

PA

MR

1, P

LAT,

PR

OC

R, T

FPI,

TFPI

2, T

SPA

N12

, TSP

AN

13

Blo

od c

oagu

latio

n (G

O:0

0075

96)

1210

Res

pons

e to

stre

ss

(GO

:000

6950

)

CD

97, C

REM

, DN

AJA

3, D

NA

JB14

, D

NA

JB9,

DU

SP10

, ED

NR

B, G

PR12

5,

GPR

39, G

PR56

, GPX

3, H

SPA

5,

HSP

B8,

HY

OU

1, IT

PR3,

LIF

, NPT

X1,

N

R4A

2, P

GF,

PPA

RG

, PR

KA

A2,

R

IPK

3, S

OD

3, T

AC

R1,

VEG

FA,

VEG

FC

AN

KR

D22

, BD

KR

B1,

ED

NR

B,

GPR

39, G

PR56

, HSP

B8,

IER

3,

ITPR

3, L

IF, L

IMK

1, N

PTX

1,

PGF,

PPA

RG

, RIP

K3,

SO

D3,

ST

IP1,

TA

CR

1, V

EGFC

Res

pons

e to

stre

ss

(GO

:000

6950

)26

18

Res

pons

e to

to

xic

subs

tanc

e (G

O:0

0096

36)

AB

HD

6, G

PX3

Res

pons

e to

toxi

c su

bsta

nce

(GO

:000

9636

)2




App

endi

x Ta

ble

2: D

own-

regu

late

d tr

ansc

ript

s and

bio

logi

cal,

onto

logy

-bas

ed a

naly

ses i

n tr

ieth

ylen

e gl

ycol

dim

etha

cryl

ate-

trea

ted

dent

al p

ulp

cells

Bio

logi

cal

proc

ess

(dow

nreg

ulat

ed)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Apo

ptot

ic

proc

ess

(GO

:000

6915

)

3233

4.4

3,9

Indu

ctio

n of

apo

ptos

is

(GO

:000

6917

)

CA

CU

L1, C

NTN

3, F

OS,

MX

RA

5,

NEX

N, R

SF1,

STK

17B

, TN

FSF1

0,

TNS3

, TR

AF5

, VC

AM

1

BO

C, C

AC

UL1

, DA

PK1,

FA

F2, F

OS,

M

XR

A5,

NEX

N, R

SF1,

TR

AF5

, VC

AM

1In

duct

ion

of a

popt

osis

(G

O:0

0069

17)

1110

Neg

ativ

e re

gula

tion

of a

popt

otic

pr

oces

s (G

O:0

0430

66)

AK

T3, I

L6, I

L7, L

OX

, MD

M2,

STA

T1,

STAT

2, Z

FHX

3FA

M19

5B, F

HL1

, IL7

, LM

O4,

LO

XN

egat

ive

regu

latio

n of

apo

ptot

ic p

roce

ss

(GO

:004

3066

)

85

Bio

logi

cal

adhe

sion

(G

O:0

0226

10)

8810

012

.211

,8Ce

ll ad

hesio

n (G

O:0

0071

55)

AD

AM

TS1,

AD

AM

TS2,

AD

AM

TS5,

A

LCA

M, A

NG

PT1,

AN

GPT

L1, A

SPN

, B

GN

, BM

P1, C

1QTN

F5, C

AD

M1,

C

NTN

3, C

OL1

1A1,

CO

L12A

1,

CO

L14A

1, C

OL1

5A1,

CO

L16A

1,

CO

L1A

1, C

OL2

7A1,

CO

L3A

1,

CO

L4A

1, C

OL4

A2,

CO

L5A

1,

CO

L5A

2, C

OL6

A1,

CO

L8A

2, C

TGF,

C

THR

C1,

DC

N, E

CM

2, E

DIL

3,

FAT1

, FLR

T2, F

MO

D, F

ND

C3B

, G

PC6,

HEP

H, H

MC

N1,

ICA

M1,

IT

GA

11, I

TGA

8, IT

GB

8, IT

GB

L1,

JUP,

KIR

REL

3, K

RA

S, L

AM

A2,

LO

X,

LRR

C15

, LR

RC

17, L

RR

C3,

LU

M,

MC

AM

, MEG

F8, M

FAP4

, MX

RA

5,

NED

D9,

NEG

R1,

NET

O2,

NEX

N,

NR

AS,

NR

P2, N

TM, N

TN1,

OM

D,

PALL

D, P

APP

A, P

DG

FD, P

KP4

, PO

DN

L1, P

OST

N, P

PFIA

1, R

RA

S2,

SDC

2, S

IPA

1L1,

SLI

T2, S

LITR

K6,

SP

EG, S

VEP

1, T

ENM

2, T

ENM

3,

TLR

3, T

NFA

IP6,

TN

S3, V

CA

M1,

V

CA

N, V

IT, V

WC

E

AD

AM

TS1,

AD

AM

TS12

, AD

AM

TS3,

A

DA

MTS

5, A

DA

MTS

9, A

LCA

M, A

NG

PT1,

A

RH

GEF

2, A

SAP3

, ASP

N, B

GN

, BM

P1,

BO

C, C

1QTN

F5, C

AD

M1,

CD

C42

BPA

, C

FB, C

NTN

AP1

, CO

L11A

1, C

OL1

2A1,

C

OL1

4A1,

CO

L15A

1, C

OL1

A1,

CO

L1A

2,

CO

L27A

1, C

OL3

A1,

CO

L4A

1, C

OL4

A2,

C

OL5

A1,

CO

L5A

2, C

OL6

A1,

CO

L8A

2,

CTG

F, C

THR

C1,

DA

PK1,

DC

N, D

IRA

S3,

ECM

2, E

DIL

3, F

LRT2

, FM

OD

, FN

DC

3B,

FYN

, GPC

6, H

EPH

, HM

CN

1, IC

AM

1,

ITG

A11

, ITG

A7,

ITG

B8,

ITG

BL1

, JA

G1,

JA

K1,

JUP,

KIR

REL

3, K

RA

S, L

AM

A2,

LE

PRE1

, LIN

7A, L

OX

, LR

IG3,

LR

RC

15,

LRR

C17

, LSA

MP,

LU

M, M

CA

M, M

EGF8

, M

FAP4

, MX

RA

5, N

EDD

9, N

EGR

1, N

EXN

, N

RP2

, NTM

, NTN

1, O

BSL

1, O

MD

, PA

LLD

, PA

PLN

, PA

PPA

, PC

OLC

E, P

DG

FD, P

KP4

, PO

DN

, PO

STN

, PPF

IA1,

RA

SD1,

SD

C2,

SI

PA1L

1, S

LIT3

, SM

AP1

, SPE

G, T

ENM

2,

TEN

M3,

TLR

3, T

NFA

IP6,

VC

AM

1, V

CA

N,

VIT

, VW

CE

Cel

l‑cel

l adh

esio

n (G

O:0

0163

37)

4650

Cel

l‑mat

rix

adhe

sion

(G

O:0

0071

60)

1921

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Bio

logi

cal

regu

latio

n (G

O:0

0650

07)

155

184

21.5

21,8

Hom

eosta

tic

proc

ess

(GO

:004

2592

)

ATP1

0A, A

TP2B

4, C

OL1

1A1,

C

OL1

5A1,

CO

L16A

1, C

OL1

A1,

C

OL3

A1,

CO

L4A

1, C

OL4

A2,

C

OL5

A1,

CO

L5A

2, C

OL6

A1,

CO

L8A

2

ATP2

B4,

CO

L11A

1, C

OL1

5A1,

CO

L1A

1,

CO

L1A

2, C

OL3

A1,

CO

L4A

1, C

OL4

A2,

C

OL5

A1,

CO

L5A

2, C

OL6

A1,

CO

L8A

2,

EDN

RA

Cel

lula

r cal

cium

io

n ho

meo

stas

is

(GO

:000

6874

)

21

Cel

lula

r glu

cose

ho

meo

stas

is

(GO

:000

1678

)

1

regu

latio

n of

liqu

id

surf

ace

tens

ion

(GO

:005

0828

)

1111

Reg

ulat

ion

of b

iolo

gica

l pr

oces

s (G

O:0

0507

89)

AD

M, A

FF3,

AJU

BA

, AK

T3, A

TRX

, B

CL1

1A, B

CLA

F1, C

BX

5, C

CN

L1,

CEB

PD, C

HD

3, C

HD

4, C

LIC

4,

CR

EB1,

EG

R1,

EG

R2,

EG

R3,

ELF

1,

ETV

6, E

TV7,

FLI

1, F

OS,

FO

XO

3,

FOX

P1, G

LI2,

GN

AQ

, ID

4, IF

I16,

IL6,

IL

7, IR

F7, I

RX

3, JD

P2, J

MJD

1C, J

UN

, JU

P, K

CN

T2, K

LF12

, KLF

13, K

LF2,

K

LF6,

KLF

7, K

LF9,

KR

CC

1, L

DB

2,

LOX

, MA

F, M

AFB

, MD

M2,

MEF

2C,

MEO

X1,

MG

A, M

ME,

MSX

2, N

FAT5

, N

R3C

2, N

R4A

1, P

DG

FA, P

DLI

M1,

PE

AR

1, P

HC

1, P

PAR

GC

1A, P

RD

M1,

PR

RX

1, P

SD3,

RA

SAL2

, RG

S12,

R

SF1,

RU

NX

1T1,

RU

NX

2, R

YB

P,

SCM

L1, S

ERPI

NF1

, SER

PIN

H1,

SIX

1,

SKI,

SLIT

2, S

LITR

K6,

SM

AD

6, S

OX

4,

SP10

0, S

P110

, STA

T1, S

TAT2

, TA

C1,

TB

X3,

TC

F4, T

CF7

L2, T

OX

, TSC

22D

3,

VD

R, Z

BTB

20, Z

BTB

38, Z

FHX

3,

ZFP9

1, Z

NF1

48, Z

NF2

2, Z

NF2

4,

ZNF4

62, Z

NF7

11, Z

NFX

1, Z

SCA

N31

AD

M, A

DM

2, A

FF3,

AJU

BA

, ATF

3,

ATF4

, ATR

X, B

AR

X1,

BC

L11A

, BC

LAF1

, C

BX

5, C

CN

L1, C

EBPG

, CH

D3,

CH

D4,

C

LIC

3, C

LIC

4, C

REB

1, D

DX

3Y, D

DX

43,

DU

SP1,

ED

NR

A, E

GR

1, E

GR

2, E

GR

3,

EIF2

S3, E

IF4G

1, E

IF5,

ELF

1, E

LF2,

ETV

6,

FAM

195B

, FH

L1, F

LI1,

FO

S, F

OX

C1,

FO

XO

3, F

OX

P1, F

ZD4,

GLI

2, G

LI3,

G

NA

I2, G

NA

Q, G

SC, H

MG

B1,

HR

, ID

4,

IFI1

6, IL

7, IR

X3,

JAG

1, JD

P2, J

UP,

KC

NT2

, K

LF12

, KLF

13, K

LF2,

KLF

6, K

LF7,

KLF

9,

KR

CC

1, L

DB

2, L

MO

4, L

OX

, MA

F, M

AFB

, M

EF2C

, MM

E, N

CO

A1,

NFA

T5, N

R3C

1,

NR

4A1,

NR

4A3,

PD

GFA

, PD

LIM

1, P

EAR

1,

PHC

1, P

PAR

GC

1A, P

RD

M1,

PR

RX

1,

PSD

3, P

TGIS

, RA

SAL2

, RG

S2, R

GS4

, R

GS5

, RSF

1, R

UN

X1T

1, R

UN

X2,

RY

BP,

SA

TB1,

SC

ML1

, SER

PIN

B9,

SER

PIN

F1,

SER

PIN

H1,

SIX

1, S

KI,

SLIT

3, S

MA

D6,

SM

AR

CA

1, S

MO

, SO

X4,

SP1

10, T

BX

3,

TCF4

, TC

F7L1

, TC

F7L2

, TEA

D2,

TO

X,

TRPS

1, T

SC22

D3,

TW

IST1

, WN

T5A

, ZB

TB20

, ZB

TB38

, ZN

F148

, ZN

F22,

ZN

F462

, ZN

F618

, ZN

F711

, ZN

FX1,

ZS

CA

N31

Neg

ativ

e re

gula

tion

of a

popt

otic

pro

cess

(G

O:0

0430

66)

85

Reg

ulat

ion

of

nucl

eoba

se‑

cont

aini

ng

com

poun

d m

etab

olic

pro

cess

(G

O:0

0192

19)

8796

regu

latio

n of

ph

osph

ate

met

abol

ic p

roce

ss

(GO

:001

9220

)

47

Reg

ulat

ion

of tr

ansl

atio

n (G

O:0

0064

17)

17

Reg

ulat

ion

of

vaso

cons

trict

ion

(GO

:001

9229

)

35

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Reg

ulat

ion

of m

olec

ular

fu

nctio

n (G

O:0

0650

09)

AB

I2, A

DA

MTS

1, A

DA

MTS

2,

AD

AM

TS5,

AK

AP9

, BM

P1, C

AR

D16

, C

ASP

1, C

CD

C10

2B, C

CN

JL, C

CN

L1,

CD

KN

1C, C

DK

N2B

, CEP

68, C

HN

1,

CST

A, E

DIL

3, F

BLI

M1,

FN

DC

3B,

GA

PVD

1, G

NA

Q, H

EPH

, ITI

H5,

IT

SN2,

LPP

, MY

H10

, MY

H11

, M

YO

1D, M

YO

6, N

AP1

L3, N

ETO

2,

NR

P2, P

DG

FA, P

DG

FD, P

DP1

, PH

AC

TR2,

PPM

1H, P

PP1R

12A

, PP

P1R

14A

, PSD

3, R

ASA

L2, R

GS1

2,

RU

FY3,

SEL

1L3,

SER

PIN

F1,

SER

PIN

H1,

SIP

A1L

1, S

TAU

2

AD

AM

TS1,

AD

AM

TS12

, AD

AM

TS3,

A

DA

MTS

5, A

DA

MTS

9, A

DA

RB

1, A

KA

P9,

ARH

GA

P28,

ARH

GA

P5, A

RH

GEF

2, A

SAP3

, BI

RC6,

BM

P1, C

CDC1

02A

, CC

NJL

, CC

NL1

, CD

KN

1C, C

EP68

, CH

N1,

CN

TNA

P1,

CSTA

, ED

IL3,

FA

RP1,

FB

LIM

1, F

ND

C3B

, G

APV

D1,

GN

AI2

, GN

AQ

, HEP

H, I

TIH

5,

ITSN

2, L

RRC8

B, M

YH

10, M

YH

11, M

YO

6,

NA

P1L3

, NRP

2, O

BSL1

, PA

PLN

, PC

OLC

E,

PDG

FA, P

DG

FD, P

PP1R

12A

, PPP

1R14

A,

PSD

3, R

ALB

P1, R

ASA

L2, R

ASS

F4, R

GS2

, RG

S4, R

GS5

, RIM

S3, R

NA

SE4,

RU

FY3,

SE

L1L3

, SER

PIN

B9, S

ERPI

NF1

, SER

PIN

H1,

SE

STD

1, S

IPA

1L1,

SLP

I, SM

AP1

Reg

ulat

ion

of

cata

lytic

act

ivity

(G

O:0

0507

90)

4862

Cel

lula

r co

mpo

nent

or

gani

zatio

n or

bio

gene

sis

(GO

:007

1840

)

7074

9.7

8,8

Cel

lula

r co

mpo

nent

bi

ogen

esis

(G

O:0

0440

85)

AD

D3,

HSP

H1,

NLG

N4Y

, WA

SF2

AD

D3,

HSP

A5,

WA

SF1,

WA

SF2

Prot

ein

com

plex

bi

ogen

esis

(G

O:0

0702

71)

34

Cel

lula

r co

mpo

nent

or

gani

zatio

n (G

O:0

0160

43)

ACT

A2,

ACT

R2, A

KT3

, ATR

X,

C1Q

TNF5

, CA

LD1,

CBX

5, C

CDC1

02B,

CH

D3,

CH

D4,

CO

L11A

1, C

OL1

5A1,

CO

L16A

1, C

OL1

A1,

CO

L27A

1,

COL3

A1,

CO

L4A

1, C

OL4

A2,

CO

L5A

1,

COL5

A2,

CO

L6A

1, C

OL8

A2,

CT

HRC

1, D

MD

, DSP

, DST

, DY

NC1

H1,

D

YN

C1LI

2, E

ZR, F

AT1,

FBL

IM1,

FR

MD

4A, I

NG

3, JU

P, K

IF6,

KRT

7,

LIM

A1,

LM

OD

1, L

PP, M

X1,

MX

2,

MY

H10

, MY

H11

, MY

O1D

, MY

O6,

N

AP1

L3, N

LGN

4Y, O

LFM

L3, P

DLI

M1,

PH

ACT

R2, R

DX

, RU

NX

1T1,

SET

BP1,

SM

C3, S

ORB

S2, S

P100

, SP1

10,

SPTB

N1,

SY

NPO

2, T

LN1,

TO

X, T

PM1,

TP

M4,

TU

BA1A

, TU

BB2A

, WIS

P1,

ZFH

X3

AC

TA2,

AC

TG2,

AC

TR2,

AN

K2,

ATR

X,

BA

Z2B

, BR

D4,

C1Q

TNF5

, CA

LD1,

CB

X5,

C

CD

C10

2A, C

DC

42B

PA, C

HD

3, C

HD

4,

CO

L11A

1, C

OL1

5A1,

CO

L1A

1, C

OL1

A2,

C

OL2

7A1,

CO

L3A

1, C

OL4

A1,

CO

L4A

2,

CO

L5A

1, C

OL5

A2,

CO

L6A

1, C

OL8

A2,

C

THR

C1,

DB

N1,

DM

D, D

SP, D

ST,

DY

NC

1H1,

DY

NC

1LI2

, EZR

, FB

LIM

1,

FHL1

, FO

XC

1, H

MG

B1,

ING

3, JU

P,

KRT

7, L

IMA

1, L

IN7A

, LM

O4,

LM

OD

1,

MK

NK

2, M

YH

10, M

YH

11, M

YO

6,

NA

P1L3

, OLF

ML2

A, O

LFM

L3, P

DLI

M1,

R

UN

X1T

1, S

ETB

P1, S

ETD

8, S

MA

RC

A1,

SM

C3,

SM

C4,

SO

RB

S2, S

P110

, SY

NPO

2,

TLN

1, T

OP1

, TO

P2A

, TO

X, T

PM1,

TU

BE1

, W

ISP1

, ZA

K

Cel

lula

r com

pone

nt

mor

phog

enes

is

(GO

:003

2989

)

4644

Org

anel

le

orga

niza

tion

(GO

:000

6996

)

1320

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Cel

lula

r pro

cess

(G

O:0

0099

87)

332

371

46.0

43,9

Cel

l co

mm

unic

atio

n (G

O:0

0071

54)

ABI

2, A

DA

MTS

1, A

DA

MTS

2,

AD

AM

TS5,

AFF

3, A

KT3

, ALC

AM

, A

LPK

2, A

NG

PT1,

AN

GPT

L1,

ASP

N, B

GN

, BM

P1, B

MP4

, BM

PR2,

CA

CNA

1C, C

AD

M1,

CA

P2,

CCD

C102

B, C

DK

11A

, CD

K6,

CEP

68,

CHN

1, C

HRN

A9,

CLI

C4, C

NTN

3,

COL1

1A1,

CO

L15A

1, C

OL1

6A1,

CO

L1A

1, C

OL3

A1,

CO

L4A

1, C

OL4

A2,

CO

L5A

1, C

OL5

A2,

CO

L6A

1, C

OL8

A2,

CR

EB1,

CTG

F, C

THRC

1, C

XCL

1,

CXCL

10, C

XCL

6, C

XCR

7, D

CN,

DTX

3L, D

YN

C1LI

2, E

DIL

3, E

FNB2

, EL

F1, E

TV6,

ETV

7, F

ABP

3, F

AT1,

FB

N1,

FBN

2, F

ER, F

GF1

, FG

F7, F

LI1,

FL

RT2,

FN

DC3

B, F

OX

O3,

GA

DD

45B,

G

DF5

, GH

R, G

NA

Q, G

NG

12, G

PR12

4,

GPR

133,

GPR

183,

GRI

A3,

HEP

H,

HTR

A1,

IFI3

5, IL

6, IL

6ST,

IL7,

INH

BA,

INH

BE, I

TGB8

, ITG

BL1,

ITSN

2, JU

N,

JUP,

KCN

MB1

, KRA

S, L

AM

A2,

LEP

R,

LIM

S2, L

OX

, LPH

N2,

LPP

R4, L

RRC1

5,

LRRC

17, L

RRC3

, LTB

P2, M

ARC

KS,

M

CAM

, MEG

F8, M

FAP4

, MM

E,

MO

RN2,

MX

RA5,

MY

H10

, MY

H11

, M

YO

1D, M

YO

6, N

ETO

2, N

MI,

NR3

C2,

NR4

A1,

NRA

S, N

RP2,

NTN

1, O

LFM

L3,

PAPP

A, P

DE7

B, P

DG

FA, P

DG

FD,

PDP1

, PEA

R1, P

HLD

B2, P

KN

2, P

KP4

, PL

XN

A2,

PLX

NC1

, PLX

ND

1, P

OD

NL1

, PO

STN

, PPA

P2B,

PPM

1H, P

RKCI

, PR

KG

1, P

TGD

S, P

TGER

2, P

TGER

4,

PTG

FR, P

TK7,

PTN

, PTP

LA, P

TPRD

, PX

K, R

ASA

L2, R

CAN

2, R

HO

BTB1

,

ACV

R2A

, AD

AM

TS1,

AD

AM

TS12

, A

DA

MTS

3, A

DA

MTS

5, A

DA

MTS

9, A

FF3,

A

LCA

M, A

LPK

2, A

NG

PT1,

ARH

GEF

2,

ASA

P3, A

SPN

, BG

N, B

MP1

, BM

P4, B

MPR

2,

BOC,

CA

DM

1, C

AP2

, CBL

B, C

CDC1

02A

, CD

C42B

PA, C

DK

11A

, CD

K6,

CEP

68, C

FB,

CHN

1, C

HRN

A1,

CLI

C3, C

LIC4

, CN

TNA

P1,

COL1

1A1,

CO

L15A

1, C

OL1

A1,

CO

L1A

2,

COL3

A1,

CO

L4A

1, C

OL4

A2,

CO

L5A

1,

COL5

A2,

CO

L6A

1, C

OL8

A2,

CRE

B1, C

TGF,

CT

HRC

1, C

XCL

6, C

XCR

7, C

YSL

TR1,

DCN

, D

EPD

C1, D

IRA

S3, D

YN

C1LI

2, E

DIL

3,

EDN

RA, E

FNB2

, ELF

1, E

LF2,

ETV

6, F

AF2

, FA

M19

5B, F

BN1,

FBN

2, F

ER, F

GF1

, FG

F7,

FLI1

, FLR

T2, F

ND

C3B,

FO

XC1

, FO

XO

3,

FYN

, FZD

4, G

NA

I2, G

NA

Q, G

NG

12, G

NG

2,

GPC

PD1,

GPR

124,

GPR

133,

GPR

183,

GPR

64,

GRI

A3,

HEP

H, H

MG

B1, H

TRA

1, IL

11RA

, IL

20RB

, IL6

ST, I

L7, I

NH

BA, I

NH

BE, I

RAK

3,

ISLR

, ITG

B8, I

TGBL

1, IT

SN2,

JAG

1, JA

K1,

JU

P, K

RAS,

KRE

MEN

1, L

AM

A2,

LEP

R,

LEPR

E1, L

IMS2

, LO

X, L

PHN

2, L

PPR4

, LR

IG3,

LRR

C15,

LRR

C17,

LRR

C8B,

LTB

P1,

LTBP

2, L

TBP4

, MA

RCK

S, M

CAM

, MEG

F10,

M

EGF8

, MFA

P4, M

IB1,

MK

NK

2, M

ME,

M

XRA

5, M

YH

10, M

YH

11, M

YO

6, N

COA

1,

NR3

C1, N

R4A

1, N

R4A

3, N

RP2,

NTN

1,

OBS

L1, O

LFM

L2A

, OLF

ML3

, PA

PLN

, PA

PPA

, PCO

LCE,

PD

E4B,

PD

E4D

, PD

E7B,

PD

GFA

, PD

GFD

, PEA

R1, P

HLD

B2, P

IM1,

PK

N2,

PK

P4, P

LXN

A4,

PLX

NC1

, PLX

ND

1,

POD

N, P

OST

N, P

PAP2

B, P

PP2R

5E, P

RKCI

, PR

KG

1, P

TGD

S, P

TGER

2, P

TGER

4, P

TGFR

, PT

K7,

PTN

, PTP

RD, P

XK

, RA

SAL2

, RA

SD1,

RA

SSF4

, RCA

N1,

RH

OA

, RH

OB

TB1,

R

HO

BTB

3, R

HO

Q,

Cel

l‑cel

l sig

nalin

g (G

O:0

0072

67)

4647

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

RH

OB

TB3,

RH

OQ

, RR

AS2

, RU

FY3,

R

UN

X2,

S1P

R1,

SC

G5,

SD

C2,

SE

MA

3C, S

H3P

XD

2A, S

KI,

SLC

1A3,

SL

IT2,

SLI

TRK

6, S

MA

D6,

SN

TB1,

SN

TB2,

SO

RB

S2, S

P100

, SP1

10,

SPA

RC

, STA

T1, S

TAT2

, SV

2A, S

VEP

1,

SYN

J2B

P, T

AC

1, T

AC

STD

2, T

CF7

L2,

TEN

M2,

TEN

M3,

TG

FB2,

TLR

3,

TMTC

1, T

NFA

IP6,

TN

FSF1

0, T

NFS

F4,

TNS3

, TO

X, T

RA

F5, V

CA

M1,

WIS

P1,

WN

K1

RIM

S3, R

PS6K

A2,

RU

FY3,

RU

NX

2,

S1PR

1, S

CG

5, S

DC

2, S

EMA

3C, S

EMA

3D,

SEST

D1,

SH

3PX

D2A

, SK

I, SL

C1A

3,

SLC

1A4,

SLC

6A9,

SLI

T3, S

MA

D6,

SM

AP1

, SM

O, S

NTB

1, S

NTB

2, S

OR

BS2

, SP1

10,

SPA

RC

, SV

2A, T

CF7

L1, T

CF7

L2, T

ENM

2,

TEN

M3,

TG

FB2,

TG

FB3,

TLR

3, T

MTC

4,

TNFA

IP6,

TO

X, T

RA

F5, T

RIB

2, T

RIB

3,

TRPC

6, U

NC

5D, V

CA

M1,

WIS

P1, W

NK

1,

WN

T5A

, WSB

1, Z

AK

, ZFP

36L1

Cel

l cyc

le

(GO

:000

7049

)A

BI2

, AC

TA2,

AC

TR2,

AK

T3, B

ICC

1,

CA

CU

L1, C

ALD

1, C

CD

C10

2B,

CC

NJL

, CC

NL1

, CD

K11

A, C

DK

6,

CD

KN

1C, C

DK

N2B

, CN

TN3,

C

TGF,

DD

X60

L, D

KC

1, D

NA

JC1,

D

YN

C1H

1, D

YN

C1L

I2, E

GR

1,

EGR

2, E

GR

3, E

IF2A

K2,

ELF

1, E

TV6,

ET

V7,

FB

LIM

1, F

GF7

, FLI

1, F

OS,

G

AD

D45

B, I

GF2

, IN

G3,

JDP2

, JU

N,

KIF

6, L

PP, M

AF,

MA

FB, M

XR

A5,

M

YH

10, M

YH

11, M

YO

1D, M

YO

6,

NA

P1L3

, ND

N, N

EDD

9, N

UC

KS1

, PH

C1,

PR

KG

1, P

TK7,

RA

D1,

RA

D21

, R

BM

24, R

BM

S1, R

BM

S3, R

EV1,

R

FC5,

RSF

1, S

CM

L1, S

MC

3, S

TAG

2,

STA

U2,

SY

NC

RIP

, TN

S3, T

UB

A1A

, TU

BB

2A, U

BE2

J1, V

CA

M1,

WIS

P1,

ZNFX

1

AC

TA2,

AC

TG2,

AC

TR2,

AD

AR

B1,

A

RH

GEF

2, A

TF3,

BIC

C1,

BO

C, C

AC

UL1

, C

ALD

1, C

CD

C10

2A, C

CN

JL, C

CN

L1,

CD

C42

BPA

, CD

K11

A, C

DK

6, C

DK

N1C

, C

TGF,

DK

C1,

DN

AJC

1, D

YN

C1H

1,

DY

NC

1LI2

, EG

R1,

EG

R2,

EG

R3,

ELF

1,

ELF2

, ETV

6, F

AM

179B

, FB

LIM

1, F

GF7

, FL

I1, F

OS,

IGF1

, IG

F2, I

NG

3, JD

P2, M

AF,

M

AFB

, MX

RA

5, M

YH

10, M

YH

11, M

YO

6,

NA

P1L3

, ND

N, N

EDD

9, N

UC

KS1

, PH

C1,

PM

P22,

PR

KG

1, P

TK7,

RA

D1,

RA

D21

, R

ALB

P1, R

BM

47, R

BM

S1, R

BM

S3, R

EV1,

R

PS6K

A2,

RSF

1, S

CM

L1, S

ESN

2, S

ESN

3,

SMC

3, S

MC

4, S

TAG

2, S

YN

CR

IP, T

OP2

A,

TUB

E1, U

BE2

J1, V

CA

M1,

WIS

P1, Z

AK

, ZF

P36L

1, Z

NFX

1

Mei

osis

(G

O:0

0071

26)

33

Mito

sis

(GO

:000

7067

)27

28

Cel

l pr

olife

ratio

n (G

O:0

0082

83)

FER

, FO

XO

3, F

OX

P1, P

DG

FAFE

R, F

OX

C1,

FO

XO

3, F

OX

P1, F

YN

, JA

K1,

PD

GFA

Cel

l pro

lifer

atio

n (G

O:0

0082

83)

47

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Cel

lula

r co

mpo

nent

m

ovem

ent

(GO

:000

6928

)

AB

I2, C

CD

C10

2B, C

OL1

2A1,

C

OL1

4A1,

CTG

F, D

AA

M2,

DM

D,

DO

K6,

DSP

, DST

, DY

NC

1H1,

FAT

1,

FBLI

M1,

KIA

A15

98, L

IMA

1, L

IMS2

, LM

CD

1, L

PP, M

YH

10, M

YH

11,

MY

O1D

, MY

O6,

PD

GFA

, PD

LIM

1,

SLIT

2, S

LITR

K6,

SPT

BN

1, S

YN

PO2,

TP

M1,

TPM

4, T

UB

A1A

, TU

BB

2A,

VIT

, WIS

P1, Z

FHX

3

CC

DC

102A

, CD

C42

BPA

, CO

L12A

1,

CO

L14A

1, C

TGF,

DM

D, D

OK

6, D

SP, D

ST,

DY

NC

1H1,

FB

LIM

1, F

HL1

, JA

G1,

LIM

A1,

LI

MS2

, LM

CD

1, L

MO

4, M

YH

10, M

YH

11,

MY

O6,

PD

GFA

, PD

LIM

1, P

RIC

KLE

1,

SLIT

3, S

YN

PO2,

TPM

1, T

UB

E1, V

IT,

WIS

P1

Cel

lula

r com

pone

nt

mov

emen

t (G

O:0

0069

28)

3529

Chr

omos

ome

segr

egat

ion

(GO

:000

7059

)

BIC

C1,

DY

NC

1H1,

KIF

6, R

AD

21,

REV

1, S

MC

3, S

TAG

2, T

UB

A1A

, TU

BB

2A, U

BE2

J1

BIC

C1,

DY

NC

1H1,

RA

D21

, REV

1, S

MC

3,

SMC

4, S

TAG

2, T

OP2

A, T

UB

E1, U

BE2

J1C

hrom

osom

e se

greg

atio

n (G

O:0

0070

59)

1010

Cyt

okin

esis

(G

O:0

0009

10)

AC

TA2,

AC

TR2,

CC

DC

102B

, KIF

6,

MY

H10

, MY

H11

, MY

O1D

, MY

O6

AC

TA2,

AC

TG2,

AC

TR2,

CC

DC

102A

, M

YH

10, M

YH

11, M

YO

6C

ytok

ines

is

(GO

:000

0910

)8

7

Dev

elop

men

tal

proc

ess

(GO

:003

2502

)

205

218

28.4

25,8

Ana

tom

ical

st

ruct

ure

mor

phog

enes

is

(GO

:000

9653

)

AC

TA2,

AK

T3, C

1QTN

F5, C

ALD

1,

CC

DC

102B

, CO

L11A

1, C

OL1

5A1,

C

OL1

6A1,

CO

L1A

1, C

OL2

7A1,

C

OL3

A1,

CO

L4A

1, C

OL4

A2,

C

OL5

A1,

CO

L5A

2, C

OL6

A1,

C

OL8

A2,

CTH

RC

1, D

MD

, DSP

, DST

, D

YN

C1L

I2, E

ZR, F

AT1,

FB

LIM

1,

FOX

O3,

FO

XP1

, FR

MD

4A, H

MC

N1,

JU

P, K

RT7,

LIM

A1,

LM

OD

1, L

PP,

MY

H10

, MY

H11

, OLF

ML3

, PA

LLD

, PD

LIM

1, P

HA

CTR

2, R

DX

, SO

RB

S2,

SPEG

, SPT

BN

1, S

YN

PO2,

TLN

1,

TPM

1, T

PM4,

TU

BA

1A, T

UB

B2A

, W

ISP1

, ZFH

X3

AC

TA2,

AC

TG2,

AN

K2,

C1Q

TNF5

, C

ALD

1, C

CD

C10

2A, C

DC

42B

PA,

CO

L11A

1, C

OL1

5A1,

CO

L1A

1, C

OL1

A2,

C

OL2

7A1,

CO

L3A

1, C

OL4

A1,

CO

L4A

2,

CO

L5A

1, C

OL5

A2,

CO

L6A

1, C

OL8

A2,

C

THR

C1,

DB

N1,

DM

D, D

SP, D

ST, D

USP

1,

DY

NC

1LI2

, EZR

, FB

LIM

1, F

HL1

, FO

XC

1,

FOX

O3,

FO

XP1

, HM

CN

1, JU

P, K

RT7,

LI

MA

1, L

IN7A

, LM

O4,

LM

OD

1, M

YH

10,

MY

H11

, OLF

ML2

A, O

LFM

L3, P

ALL

D,

PDLI

M1,

SO

RB

S2, S

PEG

, SY

NPO

2, T

LN1,

TP

M1,

WIS

P1

Cel

lula

r com

pone

nt

mor

phog

enes

is

(GO

:003

2989

)

4644

Cel

l di

ffere

ntia

tion

(GO

:003

0154

)

FOX

O3,

FO

XP1

, JU

P, P

SD3,

TC

F7L2

FOX

C1,

FO

XO

3, F

OX

P1, F

YN

, JA

K1,

JUP,

PS

D3,

TC

F7L1

, TC

F7L2

, WN

T5A

Cel

l diff

eren

tiatio

n (G

O:0

0301

54)

510

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Dea

th

(GO

:001

6265

)A

DA

M12

, AD

AM

19, A

KT3

, CA

CU

L1,

CA

RD

16, C

ASP

1, C

BX

5, C

NTN

3,

FOS,

GA

DD

45B

, HTR

A1,

IL6,

IL7,

K

RC

C1,

LO

X, M

AG

ED4,

MD

M2,

M

XR

A5,

NA

P1L3

, ND

N, N

EXN

, R

SF1,

SK

I, ST

AT1,

STA

T2, S

TAU

2,

STK

17B

, TN

FSF1

0, T

NS3

, TR

AF5

, V

CA

M1,

ZFH

X3

AD

AM

12, A

DA

M19

, AD

AR

B1,

AD

H1B

, A

RH

GEF

2, B

OC

, CA

CU

L1, C

BX

5, D

APK

1,

DU

SP1,

EIF

4G1,

FA

F2, F

AM

195B

, FH

L1,

FOS,

FY

N, H

TRA

1, IL

7, JA

K1,

KR

CC

1,

LMO

4, L

OX

, MA

GED

4, M

XR

A5,

NA

P1L3

, N

DN

, NEX

N, R

ASS

F4, R

SF1,

SK

I, TR

AF5

, U

NC

5D, V

CA

M1

Cel

l dea

th

(GO

:000

8219

)32

33

Ecto

derm

de

velo

pmen

t (G

O:0

0073

98)

AD

AM

TS1,

ALC

AM

, BM

P1, B

MP4

, B

NC

1, B

NC

2, C

DK

6, C

HR

NA

9,

CN

TN3,

CO

L11A

1, C

OL1

5A1,

C

OL1

6A1,

CO

L1A

1, C

OL4

A1,

C

OL4

A2,

CO

L5A

1, C

OL5

A2,

C

OL6

A1,

CO

L8A

2, C

REB

1, E

DIL

3,

EFN

B2,

FA

BP3

, FAT

1, G

DF5

, GLI

2,

HEP

H, H

SPG

2, IN

HB

A, I

NH

BE,

IR

X3,

LA

MA

2, M

AM

L2, M

CA

M,

MEG

F8, M

XR

A5,

NEG

R1,

NET

O2,

N

R4A

1, N

RP2

, NTM

, NTN

1, O

LFM

L3,

PDG

FD, P

EAR

1, P

HC

1, P

OG

Z,

PPFI

A1,

PR

RX

1, P

TK7,

RB

M24

, R

BM

S1, R

BM

S3, R

TN4,

RU

NX

2,

SCM

L1, S

EMA

3C, S

LIT2

, SLI

TRK

6,

SYN

CR

IP, T

CF4

, TEN

M2,

TEN

M3,

TG

FB2,

TPM

1, T

PM4,

VC

AM

1,

VC

AN

, ZFH

X3

AD

AM

TS1,

ALC

AM

, BA

RX

1, B

MP1

, B

MP4

, BN

C1,

BN

C2,

BO

C, C

DK

6,

CH

RN

A1,

CN

TNA

P1, C

OL1

1A1,

C

OL1

5A1,

CO

L1A

1, C

OL4

A1,

CO

L4A

2,

CO

L5A

1, C

OL5

A2,

CO

L6A

1, C

OL8

A2,

C

REB

1, E

DIL

3, E

DN

RA

, EFN

B2,

FH

L1,

GLI

2, G

LI3,

GSC

, HEP

H, H

SPG

2, IF

RD

1,

INH

BA

, IN

HB

E, IR

X3,

JAG

1, L

AM

A2,

LM

O4,

LSA

MP,

MC

AM

, MEG

F8, M

XR

A5,

N

EGR

1, N

R4A

1, N

R4A

3, N

RP2

, NTM

, N

TN1,

OLF

ML2

A, O

LFM

L3, P

CO

LCE,

PD

GFD

, PEA

R1,

PH

C1,

PO

GZ,

PPF

IA1,

PR

RX

1, P

TK7,

RB

M47

, RB

MS1

, RB

MS3

, R

PS6K

A2,

RU

NX

2, S

CM

L1, S

EMA

3C,

SEM

A3D

, SLI

T3, S

YN

CR

IP, T

CF4

, TE

NM

2, T

ENM

3, T

GFB

2, T

GFB

3, T

PM1,

U

NC

5D, V

CA

M1,

VC

AN

Ecto

derm

de

velo

pmen

t (G

O:0

0073

98)

6976

Embr

yo

deve

lopm

ent

(GO

:000

9790

)

CD

K6,

FAT

1, G

LI2,

JUP,

MEF

2C,

PTK

7, R

UN

X2,

VG

LL3,

ZFH

X3

CD

C42

BPA

, CD

K6,

DU

SP1,

FH

L1, F

OX

C1,

G

LI2,

GLI

3, JU

P, L

MO

4, M

EF2C

, PTK

7,

RU

NX

2

Embr

yo

deve

lopm

ent

(GO

:000

9790

)

912

Endo

derm

de

velo

pmen

t (G

O:0

0074

92)

ELF1

DU

SP1,

ELF

1, E

LF2,

TR

PS1

Endo

derm

de

velo

pmen

t (G

O:0

0074

92)

14

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Mes

oder

m

deve

lopm

ent

(GO

:000

7498

)

AD

AM

12, A

DA

M19

, AD

AM

TS1,

A

SPN

, BG

N, B

MP1

, BM

P4, B

MPR

2,

C1Q

TNF5

, CCD

C102

B, C

DH

11,

CDH

13, C

DH

6, C

DK

6, C

EBPD

, CN

TN3,

CO

L11A

1, C

OL1

5A1,

CO

L16A

1, C

OL1

A1,

CO

L27A

1,

COL4

A1,

CO

L4A

2, C

OL5

A1,

CO

L5A

2,

COL6

A1,

CO

L8A

2, C

TGF,

CTH

RC1,

D

CN, E

DIL

3, E

FHD

1, E

LF1,

ETV

6,

ETV

7, F

BN1,

FBN

2, F

GF7

, FLI

1,

FLRT

2, F

ND

C3B,

FO

S, G

DF5

, GPR

124,

G

PR13

3, H

EPH

, HM

CN1,

INH

BA,

INH

BE, K

IRRE

L3, K

LF12

, KLF

13,

KLF

2, K

LF6,

KLF

7, K

LF9,

LPH

N2,

LR

RC15

, MEF

2C, M

EOX

1, M

GA

, M

IER1

, MSX

2, M

XRA

5, M

YH

10,

MY

H11

, NET

O2,

NFE

2L2,

NFE

2L3,

N

RP2,

OX

TR, P

ALL

D, P

CDH

7,

PCD

H9,

PD

GFD

, PD

LIM

1, P

HC1

, PH

LDB2

, PO

DN

L1, P

OST

N, P

RRX

1,

PTK

7, R

UN

X2,

SCM

L1, S

EMA

3C,

SPEG

, STA

T1, S

TAT2

, TBX

3, T

ENM

2,

TEN

M3,

TG

FB2,

TPM

1, T

PM4,

TRA

F5,

VCA

M1,

VCA

N, V

DR,

WIS

P1, Z

FHX

3,

ZHX

2

AC

VR

2A, A

DA

M12

, AD

AM

19, A

DA

MTS

1,

ASP

N, B

AR

X1,

BC

L9L,

BG

N, B

MP1

, B

MP4

, BM

PR2,

BO

C, C

1QTN

F5,

CC

DC

102A

, CD

H11

, CD

H13

, CD

K6,

C

EBPG

, CN

TNA

P1, C

OL1

1A1,

CO

L15A

1,

CO

L1A

1, C

OL2

7A1,

CO

L4A

1, C

OL4

A2,

C

OL5

A1,

CO

L5A

2, C

OL6

A1,

CO

L8A

2,

CTG

F, C

THR

C1,

DC

N, E

DIL

3, E

FHD

1,

ELF1

, ELF

2, E

TV6,

FA

RP1

, FB

N1,

FB

N2,

FG

F7, F

HL1

, FLI

1, F

LRT2

, FN

DC

3B,

FOS,

FO

XC

1, G

PR12

4, G

PR13

3, G

PR64

, G

SC, H

EPH

, HM

CN

1, IN

HB

A, I

NH

BE,

K

IRR

EL3,

KLF

12, K

LF13

, KLF

2, K

LF6,

K

LF7,

KLF

9, L

MO

4, L

PHN

2, L

RR

C15

, M

EF2C

, MX

RA

5, M

YH

10, M

YH

11, M

YL9

, N

FE2L

1, N

FE2L

2, N

FE2L

3, N

RP2

, OB

SL1,

O

XTR

, PA

LLD

, PC

DH

7, P

CO

LCE,

PD

GFD

, PD

LIM

1, P

HC

1, P

HLD

B2,

PO

DN

, PO

STN

, PR

RX

1, P

TK7,

RN

ASE

4, R

PS6K

A2,

R

UN

X2,

SC

ML1

, SEM

A3C

, SEM

A3D

, SP

EG, T

BX

3, T

ENM

2, T

ENM

3, T

GFB

2,

TGFB

3, T

PM1,

TR

AF5

, TR

PS1,

TW

IST1

, V

CA

M1,

VC

AN

, WIS

P1, W

SB1,

ZH

X2

Dig

estiv

e tra

ct

mes

oder

m

deve

lopm

ent

(GO

:000

7502

)

21

Patte

rn

specification

proc

ess

(GO

:000

7389

)

CD

K6,

GLI

2, JU

P, K

LF12

, KLF

13,

KLF

9, P

RR

X1,

STA

U2,

TEN

M2,

TE

NM

3

AD

AR

B1,

CD

K6,

FO

XC

1, G

LI2,

GLI

3,

GSC

, JU

P, K

LF12

, KLF

13, K

LF9,

OSR

2,

PRR

X1,

TEN

M2,

TEN

M3

Ant

erio

r/pos

terio

r axissp

ecification

(GO

:000

9948

)

66

Segm

ent

specification

(GO

:000

7379

)

36

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Sex

dete

rmin

atio

n (G

O:0

0075

30)

RU

NX

2, T

CF4

RU

NX

2, T

CF4

Sex

dete

rmin

atio

n (G

O:0

0075

30)

22

Syst

em

deve

lopm

ent

(GO

:004

8731

)

AD

AM

12, A

DA

M19

, AD

AM

TS1,

A

LCA

M, A

MO

T, A

NG

PT1,

AN

GPT

L1,

ASP

N, B

GN

, BM

P1, B

MP4

, BM

PR2,

B

NC

1, B

NC

2, C

1QTN

F5, C

CD

C10

2B,

CD

H11

, CD

H13

, CD

H6,

CD

K6,

C

EBPD

, CH

RN

A9,

CN

TN3,

CR

EB1,

C

SRP2

, CTG

F, C

THR

C1,

CX

CL1

, C

XC

L10,

CX

CL6

, DC

N, E

DIL

3,

EFH

D1,

EFN

B2,

ELF

1, E

PHA

3, E

TV6,

ET

V7,

FAT

1, F

BLI

M1,

FB

N1,

FB

N2,

FG

F7, F

LI1,

FLR

T2, F

ND

C3B

, FO

S,

FOX

O3,

FO

XP1

, GD

F5, G

HR

, GLI

2,

GPR

124,

GPR

133,

HEP

H, I

L6ST

, IL7

R,

INH

BA

, IN

HB

E, IR

X3,

JUP,

KIR

REL

3,

KLF

12, K

LF13

, KLF

2, K

LF6,

KLF

7,

KLF

9, L

AM

A2,

LEP

R, L

MO

D1,

LP

HN

2, L

PP, L

RR

C15

, LTB

P2, M

AF,

M

AFB

, MA

ML2

, MC

AM

, MEF

2C,

MEO

X1,

MSX

2, M

XR

A5,

MY

H10

, M

YH

11, N

EGR

1, N

ETO

2, N

FE2L

2,

NFE

2L3,

NLG

N4Y

, NR

P2, N

TM,

NTN

1, O

LFM

L3, O

XTR

, PA

LLD

, PC

DH

7, P

CD

H9,

PD

GFD

, PD

LIM

1,

PEA

R1,

PH

C1,

PH

LDB

2, P

LXN

A2,

PL

XN

C1,

PLX

ND

1, P

OD

NL1

, PO

STN

, PP

FIA

1, P

RR

X1,

PSD

3, R

BM

24,

RB

MS1

, RB

MS3

, RTN

4, R

UN

X2,

SC

ML1

, SD

C2,

SEM

A3C

, SLI

T2,

SLIT

RK

6, S

PEG

, STA

T1, S

TAT2

, SY

NPO

2, T

CF4

, TC

F7L2

, TEN

M2,

TE

NM

3, T

GFB

2, T

NFA

IP2,

TN

FSF1

0,

TPM

1, T

PM4,

TR

AF5

, VC

AN

, VD

R,

WIS

P1, Z

FHX

3, Z

HX

2

AC

VR

2A, A

DA

M12

, AD

AM

19, A

DA

MTS

1,

ALC

AM

, AN

GPT

1, A

SPN

, BA

RX

1, B

GN

, B

MP1

, B

MP4

, BM

PR2,

BN

C1,

BN

C2,

BO

C,

C1Q

TNF5

, CC

DC

102A

, CD

H11

, CD

H13

, C

DK

6, C

HR

NA

1, C

NTN

AP1

, CR

EB1,

C

SRP2

, CTG

F, C

THR

C1,

CX

CL6

, DC

N,

EDIL

3, E

DN

RA

, EFH

D1,

EFN

B2,

ELF

1,

ELF2

, EPH

A3,

EPH

A4,

ETV

6, F

AR

P1,

FBLI

M1,

FB

N1,

FB

N2,

FG

F7, F

HL1

, FL

I1, F

LRT2

, FN

DC

3B, F

OS,

FO

XC

1,

FOX

O3,

FO

XP1

, FZD

4, G

LI2,

GLI

3,

GPR

124,

GPR

133,

GPR

64, G

SC, H

EPH

, IF

RD

1, IL

11R

A, I

L6ST

, IN

HB

A, I

NH

BE,

IR

X3,

ITM

2C, J

AG

1, JU

P, K

IRR

EL3,

K

LF12

, KLF

13, K

LF2,

KLF

6, K

LF7,

K

LF9,

LA

MA

2, L

EPR

, LM

O4,

LM

OD

1,

LPH

N2,

LR

RC

15, L

SAM

P, L

TBP1

, LTB

P2,

LTB

P4, M

AF,

MA

FB, M

CA

M, M

EF2C

, M

XR

A5,

MY

H10

, MY

H11

, MY

L9,

NEG

R1,

NFE

2L1,

NFE

2L2,

NFE

2L3,

N

RP2

, NTM

, NTN

1, O

BSL

1, O

LFM

L2A

, O

LFM

L3, O

XTR

, PA

LLD

, PC

DH

7,

PCO

LCE,

PD

GFD

, PD

LIM

1, P

EAR

1, P

HC

1,

PHLD

B2,

PLX

NA

4, P

LXN

C1,

PLX

ND

1,

POD

N, P

OST

N, P

PFIA

1, P

RR

X1,

PSD

3,

RB

M47

, RB

MS1

, RB

MS3

, RN

ASE

4,

RO

R2,

RPS

6KA

2, R

UN

X2,

SC

ML1

, SD

C2,

SE

MA

3C, S

EMA

3D, S

LIT3

, SM

O, S

PEG

, SY

NPO

2, T

CF4

, TC

F7L1

, TC

F7L2

, TEN

M2,

TE

NM

3, T

GFB

2, T

GFB

3, T

NFA

IP2,

TPM

1,

TRA

F5, T

RPS

1, T

WIS

T1, U

NC

5D, V

CA

N,

WIS

P1, W

NT5

A, Z

HX

2

Ang

ioge

nesi

s (G

O:0

0015

25)

2222

Hea

rt de

velo

pmen

t (G

O:0

0075

07)

2529

Hem

opoi

esis

(G

O:0

0300

97)

1916

Mus

cle

orga

n de

velo

pmen

t (G

O:0

0075

17)

3434

Ner

vous

syst

em

deve

lopm

ent

(GO

:000

7399

)

6577

Skel

etal

syst

em

deve

lopm

ent

(GO

:000

1501

)

3438

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Gro

wth

(G

O:0

0400

07)

10.

1G

row

th

(GO

:004

0007

)

FOX

C1

Gro

wth

(G

O:0

0400

07)

1

Imm

une

syst

em p

roce

ss

(GO

:000

2376

)

104

9914

.411

,7A

ntig

en

proc

essi

ng a

nd

pres

enta

tion

(GO

:001

9882

)

ULB

P1U

LBP1

Ant

igen

pro

cess

ing

and

pres

enta

tion

(GO

:001

9882

)

11

Imm

une

resp

onse

(G

O:0

0069

55)

C1Q

TNF5

, CC

L2, C

CL7

, CC

L8,

CEB

PD, C

XC

L1, C

XC

L10,

CX

CL6

, C

XC

R7,

ELF

1, E

TV6,

ETV

7, F

LI1,

G

BP1

, GB

P2, G

BP5

, GH

R, G

PR12

4,

GPR

133,

IFI1

6, IF

I35,

IL6S

T, IL

7R,

IRF7

, KLF

12, K

LF13

, KLF

2, K

LF6,

K

LF7,

KLF

9, L

EPR

, LPH

N2,

NM

I, O

AS1

, OA

S2, O

AS3

, PA

PPA

, PH

LDB

2,

STAT

1, S

TAT2

, STA

U2,

SV

EP1,

SW

AP7

0, T

AC

1, T

NFA

IP2,

TN

FSF1

0,

TRIM

14, U

LBP1

AD

AR

B1,

C1Q

TNF5

, C1R

, CC

L11,

CC

L2,

CC

L7, C

CL8

, CFB

, CX

CL6

, CX

CR

7, E

LF1,

EL

F2, E

TV6,

FLI

1, G

BP1

, GB

P5, G

PR12

4,

GPR

133,

GPR

64, I

FI16

, IL1

1RA

, IL2

0RB

, IL

6ST,

KLF

12, K

LF13

, KLF

2, K

LF6,

KLF

7,

KLF

9, L

EPR

, LPH

N2,

PA

PPA

, PH

LDB

2,

SEST

D1,

TN

FAIP

2, U

LBP1

B c

ell‑m

edia

ted

imm

unity

(G

O:0

0197

24)

1616

Com

plem

ent

activ

atio

n (G

O:0

0069

56)

34

Nat

ural

kill

er

cell

activ

atio

n (G

O:0

0301

01)

21

Res

pons

e to

in

terf

eron

‑gam

ma

(GO

:003

4341

)

94

Mac

roph

age

activ

atio

n (G

O:0

0421

16)

CD

302,

CO

L11A

1, C

OL1

5A1,

C

OL1

6A1,

CO

L1A

1, C

OL4

A1,

C

OL4

A2,

CO

L5A

1, C

OL5

A2,

C

OL6

A1,

CO

L8A

2, C

XC

L1, C

XC

L10,

C

XC

L6, E

LF1,

ETV

6, E

TV7,

FLI

1,

GB

P1, G

BP2

, GB

P5, L

OX

, PH

LDB

2,

SDC

2, T

NFA

IP2

CD

302,

CO

L11A

1, C

OL1

5A1,

CO

L1A

1,

CO

L4A

1, C

OL4

A2,

CO

L5A

1, C

OL5

A2,

C

OL6

A1,

CO

L8A

2, C

XC

L16,

CX

CL6

, EL

F1, E

LF2,

ETV

6, F

LI1,

GB

P1, G

BP5

, IL

20R

B, L

OX

, LY

75, M

RC

2, P

HLD

B2,

SD

C2,

TN

FAIP

2

Mac

roph

age

activ

atio

n (G

O:0

0421

16)

2525

Loca

lizat

ion

(GO

:005

1179

)10

311

314

.313

,4R

NA

lo

caliz

atio

n (G

O:0

0064

03)

DY

NC

1LI2

, STA

U2

AD

AR

B1,

DY

NC

1LI2

RN

A lo

caliz

atio

n (G

O:0

0064

03)

22

Prot

ein

loca

lizat

ion

(GO

:000

8104

)

JUP,

MPD

Z, R

UFY

3JU

P, L

NX

1, R

UFY

3A

sym

met

ric

prot

ein

loca

lizat

ion

(GO

:000

8105

)

22

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Tran

spor

t (G

O:0

0068

10)

AB

CA

13, A

BC

A5,

AC

TA2,

AC

TR2,

A

KA

P9, A

P3B

1, A

TP10

A, A

TP1B

1,

ATP2

B4,

BIC

C1,

BM

P1, C

AC

NA

1C,

CC

DC

102B

, CD

302,

CEP

68, C

HR

NA

9,

CLI

C4,

CO

L11A

1, C

OL1

5A1,

C

OL1

6A1,

CO

L1A

1, C

OL3

A1,

C

OL4

A1,

CO

L4A

2, C

OL5

A1,

C

OL5

A2,

CO

L6A

1, C

OL8

A2,

C

OPZ

2, D

YN

C1H

1, D

YN

C1L

I2,

EDIL

3, E

XO

C6,

FA

BP3

, GA

PVD

1,

GJC

1, G

PR12

4, G

PR13

3, G

RIA

3,

HEP

H, I

GF2

, ITS

N2,

KC

NE3

, K

CN

K1,

KC

NK

2, K

CN

MB

1, K

CN

T2,

KC

TD15

, KIF

6, K

RA

S, L

AM

P3,

LOX

, LPH

N2,

MPD

Z, M

X1,

MX

2,

MY

H10

, MY

H11

, MY

O1D

, MY

O6,

N

ETO

2, N

RA

S, N

RP2

, OLF

ML3

, O

SBPL

8, P

APP

A, P

DG

FD, P

EAR

1,

PLSC

R1,

PPI

C, P

PP1R

14A

, PTG

DS,

PT

GER

2, P

TGER

4, P

TGFR

, PTK

7,

RA

MP1

, RH

OB

TB1,

RH

OB

TB3,

R

HO

Q, R

RA

S2, R

TN4,

RU

FY3,

SA

A1,

SE

C14

L1, S

HR

OO

M2,

SLC

1A3,

SL

C2A

12, S

LC38

A1,

SLC

38A

4,

SNX

18, S

NX

3, S

OR

BS2

, SO

RT1,

SV

EP1,

SY

NJ2

BP,

TN

FAIP

2, T

UB

A1A

, TU

BB

2A, U

SO1

AC

TA2,

AC

TG2,

AC

TR2,

AK

AP9

, AP3

B1,

A

POL6

, AQ

P1, A

RH

GEF

2, A

RL6

IP1,

AT

P2B

4, B

ICC

1, B

MP1

, CC

DC

102A

, C

D30

2, C

EP68

, CFB

, CH

RN

A1,

CLI

C3,

C

LIC

4, C

NTN

AP1

, CO

L11A

1, C

OL1

5A1,

C

OL1

A1,

CO

L1A

2, C

OL3

A1,

CO

L4A

1,

CO

L4A

2, C

OL5

A1,

CO

L5A

2, C

OL6

A1,

C

OL8

A2,

CO

PZ2,

CW

C27

, DIR

AS3

, D

YN

C1H

1, D

YN

C1L

I2, E

DIL

3, G

APV

D1,

G

PR12

4, G

PR13

3, G

PR64

, GR

IA3,

HEP

H,

IGF1

, IG

F2, I

TSN

2, K

CN

E3, K

CN

K1,

K

CN

K2,

KC

NT2

, KC

TD12

, KC

TD15

, K

RA

S, L

AM

P3, L

NX

1, L

OX

, LPH

N2,

LY

75, M

RC

2, M

YH

10, M

YH

11, M

YO

6,

NK

TR, N

RP2

, OLF

ML2

A, O

LFM

L3,

OSB

PL8,

PA

PPA

, PC

OLC

E, P

DG

FD,

PEA

R1,

PPI

C, P

PP1R

14A

, PTG

DS,

PT

GER

2, P

TGER

4, P

TGFR

, PTK

7, R

AM

P1,

RA

SD1,

RH

OA

, RH

OB

TB1,

RH

OB

TB3,

R

HO

Q, R

IMS3

, RU

FY3,

SA

A1,

SEC

14L1

, SH

RO

OM

2, S

LC1A

3, S

LC1A

4, S

LC25

A36

, SL

C26

A10

, SLC

2A12

, SLC

31A

1, S

LC38

A1,

SL

C38

A4,

SLC

39A

6, S

LC6A

9, S

NX

18,

SNX

3, S

OR

BS2

, SO

RT1,

TM

EM17

6B,

TNFA

IP2,

TR

AM

1, T

RPC

6, T

UB

E1, U

SO1,

V

PS35

Am

ino

acid

tra

nspo

rt (G

O:0

0068

65)

36

Car

bohy

drat

e tra

nspo

rt (G

O:0

0086

43)

45

Extra

cellu

lar

trans

port

(GO

:000

6858

)

24

Ion

trans

port

(GO

:000

6811

)16

21

Lipi

d tra

nspo

rt (G

O:0

0068

69)

1716

Lyso

som

al

trans

port

(GO

:000

7041

)

11

Nuc

lear

tran

spor

t (G

O:0

0511

69)

13

Nuc

leob

ase‑

cont

aini

ng

com

poun

d tra

nspo

rt (G

O:0

0159

31)

1

Pero

xiso

mal

tra

nspo

rt (G

O:0

0435

74)

22

Phos

phat

e io

n tra

nspo

rt (G

O:0

0068

17)

13

Prot

ein

trans

port

(GO

:001

5031

)68

74

Vesi

cle‑

med

iate

d tra

nspo

rt (G

O:0

0161

92)

5357

Loco

mot

ion

(GO

:004

0011

)1

10.

10,

1Lo

com

otio

n (G

O:0

0400

11)

PDG

FAPD

GFA

Loco

mot

ion

(GO

:004

0011

)1

1

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Met

abol

ic

proc

ess

(GO

:000

8152

)

336

415

46.5

49,1

Bio

synt

hetic

pr

oces

s (G

O:0

0090

58)

FOX

O3,

GN

AQ

, JU

P, S

KI,

TCF7

L2FO

XC

1, F

OX

O3,

GN

AI2

, GN

AQ

, JU

P,

MG

ST2,

SK

I, TC

F7L1

, TC

F7L2

, TO

P1,

TOP2

A

Bio

synt

hetic

pr

oces

s (G

O:0

0090

58)

511

Cat

abol

ic

proc

ess

(GO

:000

9056

)

GN

AQ

, HEC

W2,

ITC

H, P

SD3,

R

ASA

L2, R

GS1

2G

NA

I2, G

NA

Q, I

TCH

, PSD

3, R

ASA

L2,

RG

S2, R

GS4

, RG

S5, T

OP2

AC

atab

olic

pro

cess

(G

O:0

0090

56)

69

Coe

nzym

e m

etab

olic

pr

oces

s (G

O:0

0067

32)

GC

H1

GC

H1

Coe

nzym

e m

etab

olic

pro

cess

(G

O:0

0067

32)

11

Gen

erat

ion

of p

recu

rsor

m

etab

olite

s an

d en

ergy

(G

O:0

0060

91)

CY

P1B

1, C

YP7

B1,

KR

CC

1, N

OX

4,

PDP1

, SH

3PX

D2A

CY

P1B

1, C

YP7

B1,

EN

OX

1, F

MO

3,

KR

CC

1, P

TGIS

, SH

3PX

D2A

, YPE

L2G

lyco

lysi

s (G

O:0

0060

96)

1

Res

pira

tory

el

ectro

n tra

nspo

rt ch

ain

(GO

:002

2904

)

58

Nitr

ogen

co

mpo

und

met

abol

ic

proc

ess

(GO

:000

6807

)

AK

T3, F

OX

O3,

FO

XP1

, GN

AQ

, JU

P,

PSD

3, R

ASA

L2, R

GS1

2, S

KI,

TCF7

L2FO

XC

1, F

OX

O3,

FO

XP1

, GN

AI2

, GN

AQ

, G

PT2,

JUP,

PSD

3, R

ASA

L2, R

GS2

, RG

S4,

RG

S5, S

KI,

TCF7

L1, T

CF7

L2, T

OP1

, TO

P2A

Nitr

ic o

xide

bi

osyn

thet

ic

proc

ess

(GO

:000

6809

)

1

Porp

hyrin

‑co

ntai

ning

co

mpo

und

met

abol

ic p

roce

ss

(GO

:000

6778

)

1

Phos

phat

e‑co

ntai

ning

co

mpo

und

met

abol

ic

proc

ess

(GO

:000

6796

)

AB

CA

13, A

BC

A5,

AC

PL2,

GN

AQ

, LP

PR4,

OLF

ML3

, PD

GFA

, PLS

CR

1,

PPA

P2B

, PSD

3, R

ASA

L2, R

GS1

2,

SULF

1, S

ULF

2, T

NS3

DU

SP1,

GN

AI2

, GN

AQ

, LPP

R4,

O

LFM

L2A

, OLF

ML3

, PD

GFA

, PPA

P2B

, PS

D3,

RA

SAL2

, RG

S2, R

GS4

, RG

S5,

SLC

25A

36, S

ULF

1, S

ULF

2, T

OP2

A, Z

AK

Phos

phol

ipid

m

etab

olic

pro

cess

(G

O:0

0066

44)

94

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Reg

ulat

ion

of p

hosp

hate

m

etab

olic

pro

cess

(G

O:0

0192

20)

47

Prim

ary

met

abol

ic

proc

ess

(GO

:004

4238

)

AA

SS, A

BC

A13

, AB

CA

5, A

CPL

2,

AD

AM

TS1,

AD

AM

TS2,

AD

AM

TS5,

A

DC

Y9,

AD

D3,

AFF

3, A

JUB

A, A

K5,

A

KT3

, ALD

H2,

ALG

11, A

LPK

2,

AR

HG

EF10

, AR

ID5B

, ASN

S, A

TP10

A,

ATR

X, B

AC

E1, B

AC

E1, B

CAT

1,

BC

L11A

, BC

LAF1

, BIC

C1,

BM

P1,

BM

PR2,

C7o

rf10

, CA

CU

L1, C

AM

KK

2,

CA

RD

16, C

ASP

1, C

BS,

CB

X5,

C

CN

L1, C

DK

11A

, CD

K6,

CEB

PD,

CER

S6, C

H25

H, C

HD

3, C

HD

4, C

HN

1,

CH

SY3,

CLI

C4,

CN

TN3,

CPE

, CR

EB1,

C

RYA

B, C

STA

, CY

P1B

1, C

YP7

B1,

D

DX

60L,

DH

RS3

, DK

C1,

DN

AJC

1,

DPY

SL2,

DTX

3L, D

YN

C1L

I2, D

ZIP3

, ED

IL3,

EG

R1,

EG

R2,

EG

R3,

EIF

2AK

2,

ELF1

, ELO

VL2

, EN

PEP,

EPR

S, E

TV6,

ET

V7,

FA

BP3

, FER

, FK

BP1

4, F

KB

P9,

FLI1

, FN

DC

3B, F

OS,

FO

XO

3, F

OX

P1,

GC

H1,

GFP

T2, G

LI2,

GN

AQ

, GTF

2H2,

G

UC

Y1B

3, G

XY

LT2,

HA

S2, H

ECW

2,

HEP

H, H

INT3

, HM

CN

1, H

SP90

B1,

H

SPB

3, H

SPB

7, H

SPH

1, H

TRA

1, ID

4,

IFI1

6, IG

F2, I

NG

3, IN

SIG

1, IR

F7,

IRX

3, IT

CH

, ITI

H5,

JDP2

, JM

JD1C

, JU

N, J

UP,

KD

M4B

, KIA

A20

18, K

LF12

, K

LF13

, KLF

2, K

LF6,

KLF

7, K

LF9,

K

RC

C1,

LA

MP3

, LA

RP7

, LC

TL,

LDB

2, L

EPR

EL4,

LO

X, L

PPR

4,

LRR

FIP1

, MA

F, M

AFB

, MED

13L,

M

EF2C

, MEO

X1,

MES

T, M

EX3B

, M

GA

, MG

A, M

IER

1, M

ME,

AA

SS, A

CV

R2A

, AD

AM

TS1,

AD

AM

TS12

, A

DA

MTS

3, A

DA

MTS

5, A

DA

MTS

9,

AD

AR

B1,

AD

D3,

AD

H1B

, AFF

3, A

JUB

A,

ALD

H1A

1, A

LDH

1L2,

ALD

H2,

ALG

11,

ALP

K2,

APO

L6, A

RG

2, A

RH

GA

P5,

AR

HG

EF2,

AR

ID5B

, ASN

S, A

TF3,

AT

F4, A

TRX

, BA

CE1

, BA

CE1

, BA

RX

1,

BA

Z2B

, BC

AT1,

BC

L11A

, BC

LAF1

, B

ICC

1, B

MP1

, BM

PR2,

BO

C, B

RD

4, C

1R,

CA

CU

L1, C

AM

KK

2, C

BS,

CB

X5,

CC

NL1

, C

DC

42B

PA, C

DK

11A

, CD

K6,

CEB

PG,

CER

S6, C

FB, C

FD, C

H25

H, C

HD

3, C

HD

4,

CH

N1,

CH

SY3,

CLI

C3,

CLI

C4,

CN

TNA

P1,

CPE

, CPM

, CR

EB1,

CRY

AB

, CST

A,

CTH

, CTS

C, C

WC

27, C

YP1

B1,

CY

P7B

1,

DA

PK1,

DD

X3Y

, DD

X43

, DH

CR

7, D

HR

S3,

DH

X36

, DK

C1,

DN

AJC

1, D

PYSL

2, D

USP

1,

DY

NC

1LI2

, DY

RK

2, D

ZIP3

, ED

IL3,

ED

NR

A, E

GR

1, E

GR

2, E

GR

3, E

IF2S

3,

EIF4

EBP1

, EIF

4G1,

EIF

5, E

LF1,

ELF

2,

ELO

VL2

, EN

PP1,

EN

TPD

3, E

PRS,

ETV

6,

FAM

195B

, FER

, FH

L1, F

KB

P9, F

LI1,

FM

O3,

FN

DC

3B, F

OS,

FO

XC

1, F

OX

O3,

FO

XP1

, FY

N, G

CH

1, G

FPT2

, GLI

2,

GLI

3, G

NA

I2, G

NA

Q, G

PT2,

GPX

7, G

SC,

GTF

2H2,

GU

CY

1B3,

GX

YLT

2, H

6PD

, H

AD

HA

, HA

S2, H

EPH

, HM

CN

1, H

MG

B1,

H

R, H

SP90

B1,

HSP

A5,

HSP

B3,

HTR

A1,

ID

4, IF

I16,

IGF1

, IG

F2, I

NG

3, IN

SIG

1,

IRA

K3,

IRX

3, IS

G15

, ISG

20, I

TCH

, IT

IH5,

JAG

1, JA

K1,

JDP2

, JH

DM

1D, J

UP,

K

DM

4A, K

DM

4B, K

DM

5A,

Car

bohy

drat

e m

etab

olic

pro

cess

(G

O:0

0059

75)

1822

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

MSR

B3,

MSX

2, M

XR

A5,

NA

P1L3

, N

ETO

2, N

EXN

, NFA

T5, N

FE2L

2,

NFE

2L3,

NFI

B, N

FIX

, NPR

3,

NR

3C2,

NR

4A1,

NR

P2, N

SUN

6,

NU

CK

S1, O

AS1

, OA

S2, O

AS3

, OG

T,

OSB

PL8,

PA

LLD

, PA

PPA

, PA

RP1

4,

PAR

P9, P

DE7

B, P

DG

FA, P

DG

FD,

PDLI

M1,

PD

P1, P

EAR

1, P

HC

1,

PHF1

7, P

HG

DH

, PK

N2,

PLS

CR

1,

PLX

NA

2, P

LXN

C1,

PLX

ND

1, P

OG

Z,

PPA

P2B

, PPA

RG

C1A

, PPI

C, P

PM1H

, PP

P1R

12A

, PPP

1R14

A, P

RD

M1,

PR

KC

I, PR

KG

1, P

RM

T2, P

RR

X1,

PS

AT1,

PSD

3, P

TGD

S, P

TK7,

PTP

N11

, PT

PN13

, PTP

RD

, PTP

RO

, RA

D1,

R

AD

21, R

AD

23B

, RA

SAL2

, RB

M17

, R

BM

24, R

BM

S1, R

BM

S3, R

EV1,

R

FC5,

RG

S12,

RN

F144

B, R

PL27

A,

RSF

1, R

UFY

3, R

UN

X1T

1, R

UN

X2,

RY

BP,

SC

D, S

CM

L1, S

EC14

L1,

SER

BP1

, SER

PIN

F1, S

ERPI

NH

1,

SETB

P1, S

IX1,

SK

I, SL

C1A

3,

SLC

2A12

, SLC

38A

1, S

LC38

A4,

SLI

T2,

SLIT

RK

6, S

MA

D6,

SM

C3,

SO

RB

S2,

SORT

1, S

OX

4, S

P100

, SP1

10, S

PEG

, ST

AT1,

STA

T2,

KIA

A20

18, K

LF12

, KLF

13, K

LF2,

KLF

6,

KLF

7, K

LF9,

KR

CC

1, L

AM

P3, L

AR

P7,

LCTL

, LD

B2,

LM

O4,

LO

X, L

PPR

4,

LRR

C8B

, LR

RFI

P1, M

AF,

MA

FB, M

AR

S,

MB

D4,

MED

13, M

ED13

L, M

EF2C

, MES

T,

MEX

3B, M

GST

2, M

IB1,

MID

2, M

KN

K2,

M

ME,

MSR

B3,

MX

RA

5, N

AP1

L3, N

CO

A1,

N

EXN

, NFA

T5, N

FE2L

1, N

FE2L

2, N

FE2L

3,

NFI

B, N

FIC

, NK

TR, N

ME5

, NPR

3,

NR

3C1,

NR

4A1,

NR

4A3,

NR

P2, N

SUN

6,

NU

CK

S1, O

BSL

1, O

GT,

OSB

PL8,

OSR

2,

PALL

D, P

APL

N, P

APP

A, P

CK

2, P

CO

LCE,

PD

E4B

, PD

E4D

, PD

E7B

, PD

GFA

, PD

GFD

, PD

LIM

1, P

EAR

1, P

HC

1, P

HF1

4, P

HF1

7,

PHG

DH

, PIM

1, P

KN

2, P

LXN

A4,

PLX

NC

1,

PLX

ND

1, P

OG

Z, P

PAP2

B, P

PAR

GC

1A,

PPIC

, PPP

1R12

A, P

PP1R

14A

, PPP

2R5E

, PR

DM

1, P

RK

CI,

PRK

G1,

PR

MT2

, PR

RX

1,

PSAT

1, P

SD3,

PTG

DS,

PTG

IS, P

TK7,

PT

PN13

, PTP

RD

, PY

CR

1, R

AD

1, R

AD

21,

RA

D23

B, R

ASA

L2, R

BM

17, R

BM

25,

RB

M47

, RB

MS1

, RB

MS3

, REV

1, R

GS2

, R

GS4

, RG

S5, R

NA

SE4,

RPS

6KA

2, R

SF1,

R

SPRY

1, R

UFY

3, R

UN

X1T

1, R

UN

X2,

RY

BP,

SAT

B1,

SC

D, S

CM

L1, S

EC14

L1,

SER

PIN

B9,

SER

PIN

F1, S

ERPI

NH

1,

STA

U2,

STK

17B

, SU

LF1,

SU

LF2,

SV

EP1,

SW

AP7

0, S

YN

CR

IP, T

AN

C1,

TB

X3,

TC

ERG

1, T

CF4

, TC

F7L2

, TG

IF2,

TM

TC1,

TN

S3, T

OX

, TR

A2A

, TR

A2B

, TR

IM14

+G57

, TR

IM25

, TS

C22

D3,

UG

CG

, USP

16, U

SP18

, U

SP48

, VC

AM

1, V

DR

, WA

RS,

WA

SF2,

W

NK

1, X

RN

2, Z

BED

1, Z

BTB

20,

ZBTB

38, Z

FHX

3, Z

FP91

, ZH

X2,

ZN

F148

, ZN

F22,

ZN

F24,

ZN

F462

, ZN

F711

, ZN

FX1,

ZSC

AN

31

SETB

P1, S

ETD

8, S

HM

T2, S

IX1,

SK

I, SL

C1A

3, S

LC1A

4, S

LC25

A36

, SLC

2A12

, SL

C38

A1,

SLC

38A

4, S

LC6A

9, S

LIT3

, SL

PI, S

MA

D6,

SM

AR

CA

1, S

MC

3, S

MC

4,

SOR

BS2

, SO

RT1,

SO

X4,

SP1

10, S

PEG

, SR

SF11

, SU

LF1,

SU

LF2,

SY

NC

RIP

, TA

F3,

TAN

C1,

TB

X3,

TC

EA1,

TC

EA3,

TC

EAL7

, TC

F4, T

CF7

L1, T

CF7

L2, T

EAD

2, T

GIF

2,

THO

C2,

TM

EM17

6B, T

MTC

4, T

OP1

, TO

P2A

, TO

X, T

RA

2A, T

RA

2B, T

RA

M1,

TR

IB2,

TR

IB3,

TR

PS1,

TSC

22D

3, T

WIS

T1,

UC

HL1

, USP

13, U

SP16

, USP

33, U

SP34

,

Cel

lula

r am

ino

acid

m

etab

olic

pro

cess

(G

O:0

0065

20)

1123

Lipi

d m

etab

olic

pr

oces

s (G

O:0

0066

29)

2727

Nuc

leob

ase‑

cont

aini

ng

com

poun

d m

etab

olic

pro

cess

(G

O:0

0061

39)

147

184

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

USP

48, U

TP14

C, V

CA

M1,

WA

RS,

WA

SF1,

W

ASF

2, W

NK

1, X

POT,

XR

N2,

YPE

L2,

ZAK

, ZB

ED1,

ZB

TB20

, ZB

TB38

, ZFP

36L1

, ZH

X2,

ZN

F148

, ZN

F22,

ZN

F292

, ZN

F462

, ZN

F618

, ZN

F711

, ZN

FX1,

ZSC

AN

31

Prot

ein

met

abol

ic

proc

ess

(GO

:001

9538

)

110

138

Sulfu

r co

mpo

und

met

abol

ic

proc

ess

(GO

:000

6790

)

SULF

1, S

ULF

2C

HST

11, S

LC26

A10

, SU

LF1,

SU

LF2

Sulfu

r com

poun

d m

etab

olic

pro

cess

(G

O:0

0067

90)

24

Mul

ticel

lula

r or

gani

smal

pr

oces

s (G

O:0

0325

01)

115

128

15.9

15,1

Sing

le‑

mul

ticel

lula

r or

gani

sm

proc

ess

(GO

:004

4707

)

AD

AM

12, A

DA

M19

, AD

M, A

PBB

2,

BM

P1, B

NC

1, B

NC

2, C

AC

NA

1C,

CC

DC

102B

, CD

H11

, CD

H13

, CD

H6,

C

DK

6, C

HR

NA

9, C

NN

1, C

NN

2,

CN

N3,

CN

TN3,

CO

L11A

1, C

OL1

5A1,

C

OL1

6A1,

CO

L1A

1, C

OL4

A1,

C

OL4

A2,

CO

L5A

1, C

OL5

A2,

C

OL6

A1,

CO

L8A

2, C

REB

1, C

RYA

B,

CX

CR

7, D

HR

S3, E

CM

2, E

DIL

3, F

BN

1,

FBN

2, F

MO

D, F

ND

C3B

, FO

S, F

OX

O3,

FO

XP1

, GLI

2, G

PR12

4, G

PR13

3,

GR

IA3,

HEP

H, H

MC

N1,

HSP

B3,

H

SPB

7, H

SPG

2, H

TR2A

, ITS

N2,

JUP,

K

CN

K1,

KC

NK

2, K

CN

MB

1, K

LF12

, K

LF13

, KLF

9, K

RA

S, L

AM

A2,

LEP

R,

AD

AM

12, A

DA

M19

, AD

AR

B1,

AD

M,

AD

M2,

BM

P1, B

NC

1, B

NC

2, B

OC

, C

CD

C10

2A, C

DH

11, C

DH

13, C

DK

6,

CH

RN

A1,

CN

N1,

CN

N2,

CN

TNA

P1,

CO

L11A

1, C

OL1

5A1,

CO

L1A

1, C

OL4

A1,

C

OL4

A2,

CO

L5A

1, C

OL5

A2,

CO

L6A

1,

CO

L8A

2, C

REB

1, C

RYA

B, C

XC

R7,

D

HR

S3, D

IRA

S3, D

USP

1, E

CM

2, E

DIL

3,

EDN

RA

, FB

N1,

FB

N2,

FM

OD

, FN

DC

3B,

FOS,

FO

XC

1, F

OX

O3,

FO

XP1

, FZD

4, G

LI2,

G

LI3,

GPR

124,

GPR

133,

GPR

64, G

RIA

3,

GSC

, HEP

H, H

MC

N1,

HSP

B3,

HSP

G2,

H

TR2A

, HTR

2B, I

TSN

2, JU

P, K

CN

K1,

K

CN

K2,

KLF

12, K

LF13

, KLF

9, K

RA

S,

LAM

A2,

LEP

R, L

IN7A

, LPH

N2,

Sing

le‑m

ultic

ellu

lar

orga

nism

pro

cess

(G

O:0

0447

07)

115

128

LMO

7, L

PHN

2, L

RR

C17

, LR

RC

3,

LUM

, MEG

F8, M

ME,

MX

RA

5,

MY

H10

, MY

H11

, NET

O2,

NLG

N4Y

, N

RA

S, N

RP2

, NTN

1, O

MD

, OX

TR,

PALL

D, P

CD

H7,

PC

DH

9, P

DE7

B,

PDG

FA, P

DG

FD, P

DLI

M1,

PH

AC

TR2,

PO

STN

, PPP

1R14

A, P

RR

X1,

PSD

3,

RB

MS3

, RR

AS2

, S1P

R1,

SC

G5,

SE

MA

3C, S

LC1A

3, S

LIT2

, SLI

TRK

6,

SNTB

1, S

NTB

2, S

OR

BS2

, SPE

G,

STA

U2,

SV

2A, T

AC

1, T

AG

LN,

TCF7

L2, T

ENM

2, T

ENM

3, T

LR3,

TP

M1,

TPM

4, V

CA

M1,

WN

K1

LRIG

3, L

RR

C17

, LU

M, M

EGF8

, MM

E,

MX

RA

5, M

YH

10, M

YH

11, M

YL9

, NR

P2,

NTN

1, O

BSL

1, O

MD

, OSR

2, O

XTR

, PA

LLD

, PC

DH

7, P

CO

LCE,

PD

E4B

, PD

E4D

, PD

E7B

, PD

GFA

, PD

GFD

, PD

LIM

1, P

OST

N,

PPP1

R14

A, P

RR

X1,

PSD

3, P

TGIS

, RA

SD1,

R

BM

47, R

BM

S3, R

IMS3

, S1P

R1,

SC

G5,

SE

MA

3C, S

EMA

3D, S

ESTD

1, S

LC1A

3,

SLC

1A4,

SLC

6A9,

SLI

T3, S

MO

, SN

TB1,

SN

TB2,

SO

RB

S2, S

PEG

, SV

2A, T

AG

LN,

TCF7

L1, T

CF7

L2, T

ENM

2, T

ENM

3, T

LR3,

TP

M1,

TR

PC6,

VC

AM

1, W

NK

1, W

NT5

A

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Rep

rodu

ctio

n (G

O:0

0000

03)

2435

3.3

4,1

Ferti

lizat

ion

(GO

:000

9566

)A

DA

M12

, AD

AM

19, A

DA

MTS

1,

CR

ISPL

D2,

GLI

PR2,

VW

CE

AD

AM

12, A

DA

M19

, AD

AM

TS1,

C

RIS

PLD

1, C

RIS

PLD

2, V

WC

EFe

rtiliz

atio

n (G

O:0

0095

66)

66

Gam

ete

gene

ratio

n (G

O:0

0072

76)

AK

T3, B

MP4

, CC

NJL

, CR

ISPL

D2,

G

DF5

, GLI

PR2,

GPR

124,

GPR

133,

IN

HB

A, I

NH

BE,

JUP,

KD

M4B

, LP

HN

2, M

AG

ED4,

ND

N, S

TAU

2,

TCF4

, TG

FB2,

USP

48, Z

FHX

3

AD

AR

B1,

BM

P4, C

1R, C

CN

JL, C

FD,

CR

ISPL

D1,

CR

ISPL

D2,

FH

L1, G

PR12

4,

GPR

133,

GPR

64, I

NH

BA

, IN

HB

E, JU

P,

KD

M4A

, KD

M4B

, KD

M5A

, LM

O4,

LP

HN

2, M

AG

ED4,

ND

N, T

CF4

, TG

FB2,

TG

FB3,

USP

13, U

SP33

, USP

34, U

SP48

Fem

ale

gam

ete

gene

ratio

n (G

O:0

0072

92)

77

Sper

mat

ogen

esis

(G

O:0

0072

83)

811

Res

pons

e to

stim

ulus

(G

O:0

0508

96)

9899

13.6

11,7

Cel

lula

r de

fens

e re

spon

se

(GO

:000

6968

)

CX

CL1

, CX

CL1

0, C

XC

L6, E

LF1,

ET

V6,

ETV

7, F

LI1,

IFI3

5, L

OX

, NM

I, PH

LDB

2, S

TAT1

, STA

T2, T

NFS

F10,

U

LBP1

, ZFH

X3

CX

CL6

, ELF

1, E

LF2,

ETV

6, F

HL1

, FLI

1,

IL20

RB

, LM

O4,

LO

X, P

HLD

B2,

SES

TD1,

U

LBP1

Cel

lula

r def

ense

re

spon

se

(GO

:000

6968

)

1612

Imm

une

resp

onse

(G

O:0

0069

55)

C1Q

TNF5

, CC

L2, C

CL7

, CC

L8,

CEB

PD, C

XC

L1, C

XC

L10,

CX

CL6

, C

XC

R7,

ELF

1, E

TV6,

ETV

7, F

LI1,

G

BP1

, GB

P2, G

BP5

, GH

R, G

PR12

4,

GPR

133,

IFI1

6, IF

I35,

IL6S

T, IL

7R,

IRF7

, KLF

12, K

LF13

, KLF

2, K

LF6,

K

LF7,

KLF

9, L

EPR

, LPH

N2,

NM

I, O

AS1

, OA

S2, O

AS3

, PA

PPA

, PH

LDB

2,

STAT

1, S

TAT2

, STA

U2,

SV

EP1,

SW

AP7

0, T

AC

1, T

NFA

IP2,

TN

FSF1

0,

TRIM

14, U

LBP1

AD

AR

B1,

C1Q

TNF5

, C1R

, CC

L11,

CC

L2,

CC

L7, C

CL8

, CFB

, CX

CL6

, CX

CR

7, E

LF1,

EL

F2, E

TV6,

FLI

1, G

BP1

, GB

P5, G

PR12

4,

GPR

133,

GPR

64, I

FI16

, IL1

1RA

, IL2

0RB

, IL

6ST,

KLF

12, K

LF13

, KLF

2, K

LF6,

KLF

7,

KLF

9, L

EPR

, LPH

N2,

PA

PPA

, PH

LDB

2,

SEST

D1,

TN

FAIP

2, U

LBP1

B c

ell‑m

edia

ted

imm

unity

(G

O:0

0197

24)

1616

Com

plem

ent

activ

atio

n (G

O:0

0069

56)

34

Nat

ural

kill

er

cell

activ

atio

n (G

O:0

0301

01)

21

Res

pons

e to

in

terf

eron

‑gam

ma

(GO

:003

4341

)

94

Res

pons

e to

en

doge

nous

st

imul

us

(GO

:000

9719

)

FOX

O3,

SK

IFO

XO

3, S

KI

Res

pons

e to

en

doge

nous

st

imul

us

(GO

:000

9719

)

22

Res

pons

e to

ext

erna

l st

imul

us

(GO

:000

9605

)

AN

GPT

1, B

MP1

, CO

L12A

1,

CO

L14A

1, C

XC

L1, C

XC

L6, E

DIL

3,

HEP

H, I

TGB

8, IT

GB

L1, N

ETO

2,

NR

P2, P

APP

A, P

DG

FD, P

LSC

R1,

SV

EP1,

VIT

AN

GPT

1, B

MP1

, C1R

, CFB

, CFD

, C

NTN

AP1

, CO

L12A

1, C

OL1

4A1,

CX

CL6

, ED

IL3,

HEP

H, I

L20R

B, I

TGB

8, IT

GB

L1,

NR

P2, P

APP

A, P

CO

LCE,

PD

GFD

, VIT

Blo

od c

oagu

latio

n (G

O:0

0075

96)

1518

Cont

d...




App

endi

x Ta

ble

2: C

ontd

...B

iolo

gica

l pr

oces

s (d

ownr

egul

ated

)

Num

ber

of

gene

sPe

rcen

t of

gene

hit

agai

nst

tota

l

Subg

roup

s of

bio

logi

cal

proc

ess

Gen

esSu

bgro

ups o

f bi

olog

ical

pro

cess

Num

ber

of

gene

s

1 day

7 da

ys1 da

y7

days

1 da

y7

days

1 day

7 da

ys

Res

pons

e to

stre

ss

(GO

:000

6950

)

CEB

PD, C

REB

1, C

RYA

B, E

IF2A

K2,

FO

XO

3, G

AD

D45

B, G

PR12

4, G

PR13

3,

HSP

90B

1, H

SPB

3, H

SPB

7, H

SPH

1,

LPH

N2,

MSR

B3,

NFE

2L2,

NFE

2L3,

N

R4A

1, P

DG

FA, S

MA

D6,

STK

17B

CEB

PG, C

REB

1, C

RYA

B, E

DN

RA

, FO

XO

3,

GPR

124,

GPR

133,

GPR

64, G

PX7,

HSP

90B

1,

HSP

A5,

HSP

B3,

LPH

N2,

MK

NK

2, M

OC

OS,

M

SRB

3, N

FE2L

1, N

FE2L

2, N

FE2L

3,

NR

4A1,

NR

4A3,

PD

GFA

, SM

AD

6, Z

AK

Res

pons

e to

stre

ss

(GO

:000

6950

)20

24

Res

pons

e to

to

xic

subs

tanc

e (G

O:0

0096

36)

CLI

C4,

MES

TC

LIC

3, C

LIC

4, G

PX7,

MES

TR

espo

nse

to

toxi

c su

bsta

nce

(GO

:000

9636

)

24


Documents

Microarray Analysis of the Gene Expression Profile in