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?