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

Epigenomic Changes Have Been Implicated in a Wide Variety of Human Diseases

Neurodevelopmental disordersSchizophreniaDepression

Alzheimer’s DiseaseAddiction

Adverse health outcomesCancer

Cardiopulmonary diseaseAutoimmune disease

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

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Cumulative NIDA Epigenetics R01/R21/RC1 Grants

# 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

What is the mechanism of cocaine‐associated information transmission from father to son?

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

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SingleCell

Analysis

Current Common Fund Programs

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

Co‐Chairs: Nora Volkow (NIDA), Linda Birnbaum (NIEHS), James Battey (NIDCD)

Christine Colvis                           NCATSCarol Pontzer                               NCCAM                Grace Ault                                    NCIJennifer Couch  NCIPaul Okano  NCIRichard Piekarz NCISharon Ross  NCIMukesh Verma  NCIHemin Chin NEIElise Feingold  NHGRIMike Pazin NHGRIWeiniu Gan NHLBISusan Old  NHLBIPothur Srinivas NHLBIAnna McCormick  NIASuzana Petanceska NIAConrad Malia NIAIDNasrin Nabavi NIAIDAshley Xia  NIAIDWilliam Sharrock NIAMSGuoying Liu   NIBIB

Roderic Pettigrew NIBIBCarol Kasten‐Sportes NICHDLisa Freund NICHDSusan Taymans NICHDMark Caulder NIDAGenevieve deAlmeida‐Morris  NIDADonna Jones  NIDAJonathan Pollock  NIDADena Procaccini NIDAJoni Rutter  NIDABracie Watson NIDCDLillian Shum  NIDCRKristin Abraham NIDDKOlivier Blondel  NIDDKJessica Faupel‐Badger NIDDKPhilip Smith  NIDDKJulie Wallace NIDDKLisa Chadwick NIEHSGwen Collman NIEHSChristie Drew                                       NIEHS

Astrid Haugen                               NIEHSJerry Heindel                                 NIEHS  Laurie Johnson NIEHSKimberly McAllister NIEHSSrikanth Nadadur NIEHSKristi Pettibone NIEHSFred Tyson  NIEHSLeroy Worth  NIEHSAnthony Carter  NIGMS Andrea Beckel‐Mitchener       NIMHMichelle Freund NIMHThomas Lehner  NIMHRoger Little  NIMHAleksandra Vicentic NIMHRobert Riddle  NINDSRandall Stewart  NINDSStephanie Courchesne OSCPatricia Labosky  OSCJohanna Dwyer  ODSDeborah Olster OBSSR

Co‐Coordinators: John Satterlee (NIDA), Pat Mastin (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

Epigenome Mapping CentersGOAL: 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 regions

Generate hypotheses about function

Stamatoyannopoulos, Science 337:1190, 2012

Using Epigenomic Data to Interpret GWAS Data

+

*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

Computational Epigenomics RFA (R01)

GOAL: Computational analyses taking advantage of the publicly available reference epigenomic mapsalong with other data sets.

GRANTS: Fund 10 2-year R01s in September, 2014

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

Technology Development in Epigenetics

GOAL: Develop revolutionary technologies with the potential to significantly change epigenetics research.

•Histone dynamics (Science, Henikoff)•Single molecule epigenomics (PNAS, Soloway)•SXRT of epigenomic organization (Cell, Larabell/Lomvardas)•PET imaging of histone deacetylases (Neuroimage, Gelovani)

2008 General epigenetic technologies 2011 Epigenetic imaging 2013 Epigenetic manipulation

• Funded 10 R01s, Sept 2013

Jacob Hooker lab

Epigenomics of Human Health and Disease 

GOAL: Transform our understanding of the epigenomic basis of disease

2009 CF/IC split 2011 IC only

Total:  33 R01s, 12 ICs

Alzheimer’s Cardiovascular Environmental toxinsAsthmaCancer Insulin resistanceAutoimmuneGlaucomaPsychiatricAutismSubstance abuse

Altered epigenetic states associated with:

• Gestational age at birth (Feinberg/Fallin)• Hepatocellular carcinoma (Meltzer)• Superenhancers (Young)• Schizophrenia and bipolar disorder (Mill)• Alzheimer’s disease (Mill/Bennett)

471 total

Cumulative Epigenomics Program Publications as of August 21, 2014

Cell  25Nature    14Science    4Pu

bs

Year

Lister et al. 2009 MethylC‐seqcited 1134 times

Dena Procaccinihttp://commonfund.nih.gov/publications?pid=5

Program Integration and Outreach

Tutorials on using datasets (ASHG)

Yearly “Investigators” Meetings

International Efforts

Outline

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• International effort• Generate comprehensive sets

of reference epigenomes (1000)• Common data standards • Rapid data sharing • Understand epigenomic basis

of disease• @$125M non-US effort on

reference epigenomes, plus

IHEC Members:

US: Roadmap EpigenomicsEuropean UnionCanadaGermanyJapanSouth KoreaUS: ENCODESingapore

ItalyUnited KingdomAustralia

http://epigenomesportal.ca/ihec/grid.html

ASSAYS

CELLS/TISSUES

http://epigenomesportal.ca/ihec/grid.html

Thanks to Dena Procaccini

Outline

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Human Brain Epigenomics

More neuronalepigenomes to interpret GWAS

Validation of animal epigenetic studies in post-mortem human brain

DeJager et al. 2014 Nat Neuro epubLunnon et al. 2014 Nat Neuro epub

Epigenetic Imaging and Biomarkers

Explore epigenetic biomarkers (e.g. chronic drug exposure)?

Olfactory neurons Cerebral spinal fluid Other cell types?

Improved in vivo imaging of epigenetic enzymes or changes

Jacob Hooker lab

Jacob Hooker lab

Perdurance and Prevention

How long do epigenetic changes due to environmental exposures last?

Reversible?

Intergenerational inheritance

Validate!

Epigenetic or non-epigenetic?

You are what your grandfather ate?

Protecting epigenomes for future generations?

QUESTIONS/DISCUSSION?