Epigenomics at NIDA, NIH, and ?· John Satterlee Ph.D. ... Roadmap Epigenomics Program Co-coordinator…

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  • John Satterlee Ph.D.National Institute on Drug Abuse/NIH

    Roadmap Epigenomics Program Co-coordinator

    Epigenomics at NIDA, NIH, and Beyond

    NIDA CouncilSept 3, 2014

  • One genome

    Many cell types

    transcription factorsepigenomics

  • GENOME DISEASEEPIGENOME

    External influencesEnvironmental exposures

    Nutrition Chemical toxins

    Metals Mediators of stress

    Infection (including HIV)Drugs of abuse

    Normal processesDevelopment

    Cell differentiation Aging

    EpigenomicChangesHaveBeenImplicatedinaWideVarietyofHumanDiseases

    NeurodevelopmentaldisordersSchizophreniaDepression

    AlzheimersDiseaseAddiction

    AdversehealthoutcomesCancer

    CardiopulmonarydiseaseAutoimmunedisease

    ObesityDiabetesAIDS

  • Increasing Number of Publications in Neuroepigenetics

    Year

    Non-reviewPublications

    Dena Procaccini

  • Epigenetics and Epigenomics

    DNA modifications4 types?

    Histone modifications>150 types?

    Non-coding RNAs

    Epigenome = all of the epigenetic marks for a cell type

    Epigenetics= the study of heritable or long lasting changes that are not caused by changes in the DNA sequence

  • Epigenomic Modifications Mark Functional Genomic Elements

    Adapted from Brad Bernstein

  • Outline

    1

    2

    3

    4

  • CumulativeNIDAEpigeneticsR01/R21/RC1Grants

    # funded grants

  • Drugs of Abuse and Epigenetic Changes

    CocaineNestler lab, Science, 2010Nestler lab, PNAS 2011

    Cowan lab, Neuron, 2012

    NicotineKandel lab, Sci Transl Med, 2011 Guidotti lab, PNAS 2008

    CannabinoidsHurd lab, Biol Psych. 2012Hurd lab, Neuropsychopharm 2014Nagarkatti lab, JBC 2014

    OpioidsKreek lab,Neuropsychopharm.2008Loh and Wei lab, PNAS 2012

    MethamphetamineItzak lab, Mol Psychiatry, 2014Cadet lab, PlosOne 2014Grant lab, PlosOne 2014

    AlcoholGoldman lab, PNAS 2011Atkinson lab, PlosGenetics 2013Lanfumey lab, Mol Psych 2014

  • Why do we care about epigenetics and substance abuse?

    Molecular mechanisms of SUD

    Biomarkers

    Intergenerational effects

    Identify new targets for therapeutics

    Epigenetic therapeutics

  • Less histone acetylation

    Decreased gene expression

    More histone acetylation

    Increased gene expression

    Adapted from Marcelo Wood

    Histone acetylation controls chromatin structure and gene expression

    HAT(CBP)

    Histone AcetyltransferaseHAT (e.g. CBP)

    Histone DeacetylaseHDAC

    COMPRESSED CHROMATIN

    EXPANDED CHROMATIN

  • HDAC3 inhibitor (RGFP966) enhances extinction of cocaine-seeking behavior

    Malvaez, 2013, PNAS

    Single dose HDAC3i:

    enhances extinction of cocaine CPP

    Marcelo Wood lab. PNAS 2013, J. Neuro 2013.

  • Food availability(caloric restriction)

    Impaired glucose tolerance (F2)(Zambrano J. Physiol, 2005)

    Psychosocial stress/Social environment

    Maternal behavior (F1, F2)Response to novelty (F1, F2)(Champagne, Behav. Neuro., 2007)

    PARENTAL (F0) EXPOSURE

    PHENOTYPIC EFFECT (generation)

    Drugs of Abuse ????

    Enriched environment Enhanced LTP (F1, not F2)(Arai, J. Neuro, 2009)

    Environmental Exposures and Intergenerational Phenotypes

    Chemical toxins(endocrine disruptors)

    Male fertility (F1, F2, F3, F4)(Anway, Science, 2005)

    Anxiety/gene expression brain (F1, F2, F3)(Skinner, PLOS One 2008)

  • Intergenerational Effects of Drugs of Abuse

    EXPOSURE PHENOTYPE (generation)

    Cocaine self admin.adult malerat

    THC (i.p.)adolescentsrat

    Morphine (i.p.) adolescent femalerat

    Delayed acquisition of cocaine self-administration, male F1 progeny Vassoler et al. 2013 Nat. Neuro. 16: 42-47

    Compulsive heroin seeking and altered striatal plasticity, male F1 progenySzutorisz et al. Neuropsychopharm. 2014, 39: 1215-1323

    Increased morphine analgesia, male F1 progeny Byrnes et. Al. Brain Behav. Res 2011, 218: 200-205

  • Whatisthemechanismofcocaineassociatedinformationtransmissionfromfathertoson?

    Increased BDNF promoter acetylation in sperm of cocaine-exposed fathers.

    Cocaine can reprogramthe sperm epigenome.

    I IV VI0

    15

    30

    45

    60

    75

    AcH

    3 As

    soci

    atio

    n w

    ithBD

    NF

    Prom

    oter

    s

    BDNF Promoter

    F0 SpermSalineCocaine

    *

    **

    Vassoler et al. 2013 Nat. Neuro. 16: 42-47

  • Epigenetics and HIV Latency

  • Epigenetic Manipulation of Latent HIV

    RepressionHDACi

    Shock and Kill

    Repression

    Barton et al 2014 PLoS One 9:e102684Lucera et al, 2014 J. Virol 88:10803-12

    ?

    Lockdown

  • Outline

    1

    2

    3

    4

  • SingleCell

    Analysis

    CurrentCommon FundPrograms

    Increasing the Diversity of the NIH-Funded

    Workforce

    PROMIS:Clinical

    OutcomesAssessment

    NIHCenter for

    RegenerativeMedicine

    RegulatoryScience

    MolecularLibraries

    and Imaging

    Human Microbiome

    Protein Capture

    Pioneer AwardsNew Innovator AwardsTransformative Research AwardsEarly Independence Awards Structural

    Biology

    Bioinformatics andComputational Biology

    Building Blocks,Biological Pathways

    And Networks

    Genotype-Tissue

    Expression

    Library of Integrated Network-

    Based Cellular Signatures

    (LINCS)

    Nanomedicine

    Science ofBehaviorChange

    Gulf Oil SpillLong TermFollow Up

    Global Health

    Knockout Mouse

    Phenotyping

    NIH Medical ResearchScholars

    Bridging Interventional Development Gaps (BrIDGs)

    Big Data to Knowledge

    (BD2K)

    HCS ResearchCollaboratory

    High-RiskResearch

    NIHCommon Fund

    Health Economics

    ExRNA Communication

    http://commonfund.nih.gov/

    Metabolomics

    Undiagnosed Diseases Program

    Extracellular RNACommunication Strengthening

    the Biomedical Research

    Workforce

    Illuminating theDruggableGenome Epigenomics

  • NIH Epigenomics Working Group

    CoChairs:NoraVolkow(NIDA),LindaBirnbaum(NIEHS),JamesBattey(NIDCD)

    ChristineColvisNCATSCarolPontzerNCCAMGraceAultNCIJenniferCouch NCIPaulOkano NCIRichardPiekarz NCISharonRoss NCIMukeshVerma NCIHemin Chin NEIEliseFeingold NHGRIMikePazin NHGRIWeiniu Gan NHLBISusanOld NHLBIPothur Srinivas NHLBIAnnaMcCormick NIASuzana Petanceska NIAConradMalia NIAIDNasrin Nabavi NIAIDAshleyXia NIAIDWilliamSharrock NIAMSGuoying Liu NIBIB

    Roderic Pettigrew NIBIBCarolKastenSportes NICHDLisaFreund NICHDSusanTaymans NICHDMarkCaulder NIDAGenevievedeAlmeidaMorris NIDADonnaJones NIDAJonathanPollock NIDADenaProcaccini NIDAJoniRutter NIDABracieWatson NIDCDLillianShum NIDCRKristinAbraham NIDDKOlivierBlondel NIDDKJessicaFaupelBadger NIDDKPhilipSmith NIDDKJulieWallace NIDDKLisaChadwick NIEHSGwenCollman NIEHSChristieDrewNIEHS

    AstridHaugenNIEHSJerryHeindelNIEHSLaurieJohnson NIEHSKimberlyMcAllister NIEHSSrikanthNadadur NIEHSKristiPettibone NIEHSFredTyson NIEHSLeroyWorth NIEHSAnthonyCarter NIGMSAndreaBeckelMitchener NIMHMichelleFreund NIMHThomasLehner NIMHRogerLittle NIMHAleksandraVicentic NIMHRobertRiddle NINDSRandallStewart NINDSStephanieCourchesne OSCPatriciaLabosky OSCJohannaDwyer ODSDeborahOlster OBSSR

    CoCoordinators:JohnSatterlee(NIDA),PatMastin(NIEHS)

  • dbGAP/GEO

    Health and Disease

    Mapping Centers

    Data Coord. Center

    Functional Epigenomic

    Manipulation

    Epigenetic Assay

    Improvement

    In vivo Epigenetic

    Imaging

    Computational

    EpigenomicsNovel Marks

    NIH Roadmap Epigenomics Program

    88 grants$230M

  • EpigenomeMappingCentersGOAL: Generate comprehensive epigenomic maps for

    normal human cells and tissues

    First human methylomes (Nature 2009) 92 comprehensive epigenome datasets Data publically accessible: http://www.roadmapepigenomics.org/

  • A Diversity of Human Cells and Tissues

    http://www.roadmapepigenomics.org/

  • Integrative Analysis of 92 Roadmap Epigenomes

    Analysis Lead: Manolis Kellis, MIT/Broad

    Integrative paper:

    25 companion papers:

    Analysis of 92 epigenomes 236 authors

    detailed investigations into epigenetic marks, diseases In revision with Nature and Nature Family journals

    Lisa Chadwick, NIEHS

    Publication of Manolis Bolus in Nature mid-February?

  • The Utility of Epigenomic Information

    Functional genomic prediction

    Understanding development and differentiation

    Regenerative medicine (stem and iPS cells)

    Human disease

    Environmental exposures

    Interpreting GWAS

    Biomarkers, diagnostics and therapies

    Exploring cross-talk between epigenomic mechanisms

  • Published GWAS Hits for a Wide Variety of Diseases

    http://www.genome.gov/gwastudies/

  • Gene variants in human disease

    Epigenomic data for many normal human cell/tissue types

    77% of disease variants are in/near enhancer elements or promoters*Variants are in regulatory regions NOT protein coding regionsGenerate hypotheses about function

    Stamatoyannopoulos, Science 337:1190, 2012

    UsingEpigenomicDatatoInterpretGWASData

    +

    *DNAse I hypersensitive sites

  • Use Epigenomic Information for Normal Cells/Tissues to Identify Pathogenic Cell Types

    Identify cell typesinvolved in disease

    Stamatoyannopoulos, Science 337:1190, 2012

  • ComputationalEpigenomicsRFA(R01)

    GOAL: Computational analyses taking advantage of the publicly available reference epigenomic mapsa