CENTER FOREPIGENETICS ANDMETABOLISM

NEWSLETTERFALL2019

CEMMEMBERS

PierreBaldi,Ph.D.Tallie Z.Baram,M.D., Ph.D.BruceBlumberg, Ph.D.Emiliana Borrelli,Ph.D.Rémi Buisson,Ph.D.JohnChaput,Ph.D.XingDai, Ph.D.Michelle Digman, Ph.D.TimDowning, Ph.D.EnricoGratton, Ph.D.PeterKaiser,Ph.D.KaiKessenbrock, Ph.D.DevonLawson, Ph.D.AndrejLuptak, Ph.D.SelmaMasri,Ph.D.AliMortazavi, Ph.D.NickPannunzio,Ph.D.Suzanne Sandmeyer, Ph.D.PaoloSassone-Corsi, Ph.D.MarcusSeldin, Ph.D.Yongsheng Shi,Ph.D.Rob Spitale, Ph.D.JoanSteffan, Ph.D.Leslie Thompson, Ph.D.MarceloWood,Ph.D.Kyoko Yokomori,Ph.D.

QUARTERHIGHLIGHTS

• DevonLawson, Ph.D. and KaiKessenbrock, Ph.D.wereawarded a$4millionSeed Network grantfromthe ChanZuckerberg Initiative

• Tallie Z.Baram,M.D., Ph.D.wasawarded a$15millionConte Centergrant

• ShogoSato,Ph.D. received the NARSADYoungInvestigator grant

• TimDowning, Ph.D. received the 2019NIHDirector ’s New InnovatorAwardwith$2.2millionoffunding

• $10,000CEM SeedGrantswere awardedtoCholsoon Jang, Ph.D. andNick Pannunzio, Ph.D.

• DevonLawson, Ph.D. wastherecipient oftheVScholarAwardfromtheVFoundation

• Rémi Buisson, Ph.D. received the InnovativeDevelopment andExploratoryAward

• NickPannunzio, Ph.D., received the ACS-IRGgrant

• RobertLewisreceived the UCIrvine SchoolofMedicine Dean’s Fellowship

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

UNIVERSITYOFCALIFORNIA,IRVINE |CENTERFOREPIGENETICSANDMETABOLISM

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

YOUNG INVESTIGATORGRANT

ShogoSato,Ph.D., apostdoctoralresearcher fromtheSassone-CorsiLaboratory, received the2020– 2022NARSADYoung Investigatorgrant.Thisgrantprovidestwoyearsoffundingtopromisinginvestigators toeitherextend research fellowship trainingortobegincareers asindependent research faculty.

AWARDSANDGRANTS

CHANZUCKERBURGINITIATIVE

DevonLawson, Ph.D. andKaiKessenbrock, Ph.D.wereawarded a$4millionSeed Network grantfromtheChanZuckerberg Initiative toleadanational efforttodocumenttheintricate celltypes andstates inbreasttissue thatunderlie cancer.

Forfurther reading,pleasevisit:https://news.uci.edu/2019/07/01/uci-researchers-to-

lead-national-effort-to-build-atlas-of-human-breast-cells/

CONTECENTERGRANT

TheNational Institute ofMental Health awarded Tallie Z.Baram,M.D., Ph.D., afive-year, $15millionSilvioO.Conte Centergranttocontinue studyinghowunpredictable parental andenvironmentalsignals influence aninfant’s vulnerability tocognitive andemotionalproblems, includingaddiction andpost-traumatic stress disorder.

Forfurther reading,pleasevisit:https://news.uci.edu/2019/07/10/uci-child-neurologist-dr-tallie-z-

baram-is-awarded-15-million-conte-center-grant/

UNIVERSITYOFCALIFORNIA,IRVINE |CENTERFOREPIGENETICSANDMETABOLISM

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

AWARDSANDGRANTS

NIH:DIRECTOR’SNEWINNOVATOR

TheNational Institutes ofHealth honoredTimDowning, Ph.D.withthe 2019Director ’s New InnovatorAwardtosupportinnovative biomedical research fromearlycareer investigators. AsoneofNIH’smost prestigiousawards, theDowning Laboratorywillreceive around$2.2million infundingoverfiveyears.

Forfurther reading,pleasevisit:http://engineering.uci.edu/news/2019/10/two-uci-engineers-

named-nih-new-innovators

VSCHOLAR

Inaddition toreceiving theChanZuckerburg Initiative SeedNetwork grant,DevonLawson, Ph.D.wasalsotherecipientoftheVScholarAwardfromtheVFoundationtostudytheroleofmetabolism inbreast cancermetastasis.

ACS-IRGSEEDGRANT

NickPannunzio,Ph.D.,Assistant ProfessorofMedicineandBiological Chemistry wasthe recipient ofa$45,000seed grantthroughtheUCIrvineAmerican CancerSociety Institutional Research Grant(ACS-IRG).ThisawardwillallowDr.Pannunzio todevelop genetic assaystoquantify large-scale, oncogenic genomerearrangements inhumanBcells andfurtherdissectgenetic, environmental, andpharmacological factorsthat leadtogenome instability andcancer.

UNIVERSITYOFCALIFORNIA,IRVINE |CENTERFOREPIGENETICSANDMETABOLISM

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

AWARDSANDGRANTS

INNOVATIVEDEVELOPMENTANDEXPLORATORYAWARD

TheCaliforniaBreast Cancer Research ProgramawardedRémi Buisson, Ph.D.withtheInnovative Development andExploratoryAward.The proposedresearchwilldefine themechanisms bywhichdeveloping tumorsgenerateheterogeneity throughA3AandA3Bregulation tofillacritical knowledge gapinpreventing tumorheterogeneityandsuppressingdrugresistance.

Forfurther reading,pleasevisit:https://som.uci.edu/news_releases/mutations-responsible-for-promoting-cancer-growth.asp

CEMSEEDGRANTS

Cholsoon Jang, Ph.D. (left)andNickPannunzio,Ph.D. (right)wereselected fortheCenter forEpigenetics andMetabolism’s 2019Seed Grants.BothDr.JangandDr.Pannunzio willreceive$10,000each fortheirproposedresearch.

UCIRVINESCHOOLOFMEDICINEDEAN’SFELLOWSHIP

RobertLewis,aPh.D.student inEmiliana Borrelli’s Laboratory,wasawarded aSchoolofMedicine Dean’s Fellowship.

UNIVERSITYOFCALIFORNIA,IRVINE |CENTERFOREPIGENETICSANDMETABOLISM

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

PUBLICATIONS

Intra-individual changes inmethylome profiles:anepigenetic ‘scar’ofearly-lifeadversity? (2019)

Neuropsychopharmacology

Availableat:https://www.nature.com/articles/s41386-019-0496-3

AliMortazavi andTallie Z.Baram

Rémi BuissonResearchers discovernewwaytodiscriminate betweenmutations responsible forpromotingcancer growthandthosethatarenot

UCIrvineSchoolofMedicine

Availableat:https://som.uci.edu/news_releases/mutations-responsible-for-promoting-cancer-growth.asp

MarcusSeldin,XiaYang,andAldons J.LusisSystemsgenetics applications inmetabolism research (2019)

NatureMetabolism

Availableat:https://www.nature.com/articles/s42255-019-0132-x.pdf

Review

Circadian Clocks and Cancer: TimekeepingGoverns Cellular MetabolismAmandine Verlande1,2,3 and Selma Masri1,2,3,*

The circadian clock is a biological mechanism that dictates an array of rhythmicphysiological processes. Virtually all cells contain a functional clock whose dis-ruption results in altered timekeeping and detrimental systemic effects, includingcancer. Recent advances have connected genetic disruption of the clock withmultiple transcriptional and signaling networks controlling tumor initiation andprogression. An additional feature of this circadian control relies on cellularmetabolism, both within the tumor microenvironment and the organism system-ically. A discussion of major advances related to cancer metabolism and thecircadian clock will be outlined, including new efforts related to metabolic fluxof transformed cells, metabolic heterogeneity of tumors, and the implicationsof circadian control of these pathways.

Overview of Circadian RhythmsThe circadian clock maintains cell autonomous oscillations with a 24 hour periodicity (Figure 1and Box 1). Yet, the clock also utilizes external synchronization by cues, such as light, tem-perature, and food intake, the so-called ‘zeitgebers’ or ‘time givers’ that can adapt circadiantimekeeping. The mammalian pacemaker governs rhythms in sleep/wake cycles, feeding/fasting control, metabolism, hormone secretion, and immune function. Disruptions in biolog-ical rhythms result in numerous physiological disorders in organismal homeostasis, theconsequences of which have been linked to several pathologies, including endocrine disrup-tion, metabolic syndrome, and cancer [1]. Specifically, clinical and laboratory evidence haslong suggested that a relationship exists between the circadian clock and tumorigenesis[2], yet the precise molecular mechanisms of this connection are not fully elucidated. Interest-ingly, epidemiological evidence shows a link between hormone-dependent cancers andcircadian environmental disruption by shift work, light at night exposure, and late-night eatingbehavior [3–6]. To further support this epidemiological data, genetic disruption of the circa-dian clock in mouse models has revealed a strong link with specific cancers [7–9], thoughthe precise mechanisms related to cancer initiation versus progression remain unknown.Specifically, the role of cellular metabolism in driving these transformation events, and howthis is controlled by the clock and therefore disrupted during tumorigenesis, still requires fur-ther investigation.

This review serves to summarize the current state of knowledge regarding the links between thebiological pacemaker and cancer, in an effort to highlight new avenues for therapeutic interven-tion. Specifically, we focus on several facets of tumor metabolism that can be rewired in responseto circadian disruption. We extend our discussion of cancer metabolism to address differences inmetabolic demand of tumors, and potential heterogeneity in fuel preference. Both clinical and lab-oratory data has recently relied on use of metabolic tracing in vivo to address these complexquestions, and we highlight these efforts in terms of the power of metabolic flux and metabolicfate tracing using stable isotopes. Additionally, we discuss recent advances in teasing out howthe circadian clock is implicated in regulating several pathways linked to oncogenes and tumor

HighlightsThe circadian clock is a biologicalpacemaker mechanism that preciselycontrols rhythms in behavior andphysiological functions controllingendocrinology, metabolism, and im-mune response.

Disruption of circadian rhythms has beenreported to adversely alter normal physi-ology and results in disorders linkedto metabolism, mood regulation, sleepbehavior, and cancer.

Clinical data has shown that mutationsand changes in expression of coreclock genes is reported in severalhuman cancers.

Use of genetic mouse models and celllines have delineated the crosstalk ofthe circadian clock with several path-ways linked to oncogenes and tumorsuppressors, such as c-Myc, Ras,PTEN, and p53.

The circadian clock governs metabolicpathways regulating glucose utilization,amino acid uptake, lipogenesis, and β-oxidation. Therefore, deregulation of cir-cadian rhythms impinges onmetabolismand subsequent proliferation of cancercells, which can provide new avenuesfor therapeutic intervention.

1Department of Biological Chemistry,University of California, Irvine, CA 92697,USA2Chao Family Comprehensive CancerCenter, University of California, Irvine,CA 92867, USA3Center for Epigenetics and Metabolism,University of California, Irvine, CA 92697,USA

*Correspondence:smasri@uci.edu (S. Masri).

Trends in Endocrinology & Metabolism, July 2019, Vol. 30, No. 7 https://doi.org/10.1016/j.tem.2019.05.001 445© 2019 Published by Elsevier Ltd.

Trends in Endocrinology &Metabolism

AmandineVerlande andSelmaMasri

UNIVERSITYOFCALIFORNIA,IRVINE |CENTERFOREPIGENETICSANDMETABOLISM

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

PUBLICATIONS

Rémi Buisson,AdamLangenbucher,Danae Bowen, EugeneE.Kwan,CyrilH.Benes, LeeZou,andMichaelS.Lawrence

Passengerhotspotmutations incancer drivenbyAPOBEC3Aandmesoscale genomicfeatures (2019)

Science

Availableat:https://science.sciencemag.org/content/364/6447/eaaw2872?utm_campaign=toc_sci-mag_2019-06-27&et_rid=79777156&et_cid=2878805

ShanJiang,NorikoKamei,JessicaLBolton,Xinyi Ma,HalSStern,Tallie ZBaram,andAliMortazavi

Intra-individual methylomics detects theimpactofearly-lifeadversity (2019)

LifeScienceAlliance

Availableat:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445397/

JonathanGaucher,Kenichiro Kinouchi,NicholasCeglia,EmilieMontellier,Shahaf Peleg,CarolinaMagdalenGreco,AndreasSchmidt,Ignasi Forne,SelmaMasri,PierreBaldi,AxelImhof andPaoloSassone-Corsi,inpress

Distinct metabolic adaptationoflivercircadian pathwaystoacuteandchronicpatternsofalcohol intake

ProceedingsoftheNationalAcademyofSciences

UNIVERSITYOFCALIFORNIA,IRVINE |CENTERFOREPIGENETICSANDMETABOLISM

VISIT:HTTPS://SOM.UCI.EDU/CEM CONTACT:CEPMET@UCI.EDU

EVENTS

EPIGENETICS DAY

OurannualEpigenetics DaywillbeheldonFriday,December 6th,2019onthefirstfloorofSpragueHall.Epigenetics Daywillfeature ten,thirty-minuteseminars, including seminars byUCIrvinefaculty.

Theevent willbeginat10:00amandconclude at5:00pmwithaWineandCheese Receptionimmediately following. Lunchwillalsobeprovided.

Toview thefullprogram,please visit:https://tinyurl.com/epigenday2019

CEMSEMINARS

CharlesBrenner,Ph.D.UniversityofIowaDecember 4,2019

Titletobeannounced

Bambos Kyriacou, Ph.D.UniversityofLeicesterDecember 16,2019

Sharingclockgenes:circadianandcircatidal rhythmsinfliesandcrustacea

SteveHorvath,Ph.D.UniversityofCalifornia,LosAngeles

October23,2019Epigeneticclockstudiesinmammals