Epigenomics at NIDA, NIH, and Beyond John Satterlee Ph.D. National - - PowerPoint PPT Presentation

John Satterlee Ph.D. National Institute on Drug Abuse/NIH Roadmap Epigenomics Program Co-coordinator

Epigenomics at NIDA, NIH, and Beyond

NIDA Council Sept 3, 2014

One genome Many cell types

transcription factors epigenomics

GENOME DISEASE EPIGENOME

External influences

Environmental exposures Nutrition Chemical toxins Metals Mediators of stress Infection (including HIV) Drugs of abuse

Normal processes

Development Cell differentiation Aging

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

Neurodevelopmental disorders Schizophrenia Depression Alzheimer’s Disease Addiction

Adverse health outcomes

Cancer Cardiopulmonary disease Autoimmune disease Obesity Diabetes AIDS

Increasing Number of Publications in Neuroepigenetics

Year Non-review Publications Dena Procaccini

Epigenetics and Epigenomics

DNA modifications 4 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

Cocaine

Nestler lab, Science, 2010 Nestler lab, PNAS 2011 Cowan lab, Neuron, 2012

Nicotine

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

Cannabinoids

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

Opioids

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

Methamphetamine

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

Alcohol

Goldman lab, PNAS 2011 Atkinson 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 Acetyltransferase HAT (e.g. CBP) Histone Deacetylase HDAC

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 male rat THC (i.p.) adolescents rat Morphine (i.p.) adolescent female rat 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 progeny

Szutorisz 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 reprogram the sperm epigenome.

I IV VI 15 30 45 60 75

AcH3 Association with BDNF Promoters BDNF Promoter F0 Sperm

Saline Cocaine

* * *

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

Epigenetics and HIV Latency

Epigenetic Manipulation of Latent HIV

Repression

HDACi

“Shock and Kill” Repression

Barton et al 2014 PLoS One 9:e102684 Lucera et al, 2014 J. Virol 88:10803-12

?

“Lockdown”

Outline

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Single Cell Analysis

Current Common Fund Programs

Increasing the Diversity

• f the NIH-Funded

Workforce PROMIS: Clinical Outcomes Assessment NIH Center for Regenerative Medicine Regulatory Science Molecular Libraries and Imaging Human Microbiome Protein Capture

Pioneer Awards New Innovator Awards Transformative Research Awards Early Independence Awards

Structural Biology Bioinformatics and Computational Biology Building Blocks, Biological Pathways And Networks Genotype- Tissue Expression Library of Integrated Network- Based Cellular Signatures (LINCS) Nanomedicine Science of Behavior Change Gulf Oil Spill Long Term Follow Up Global Health Knockout Mouse Phenotyping NIH Medical Research Scholars Bridging Interventional Development Gaps (BrIDGs) Big Data to Knowledge (BD2K) HCS Research Collaboratory High-Risk Research

NIH

Common Fund

Health Economics ExRNA Communication

http://commonfund.nih.gov/

Metabolomics Undiagnosed Diseases Program Extracellular RNA Communication Strengthening the Biomedical Research Workforce Illuminating the Druggable Genome Epigenomics

NIH Epigenomics Working Group

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

Christine Colvis NCATS Carol Pontzer NCCAM Grace Ault NCI Jennifer Couch NCI Paul Okano NCI Richard Piekarz NCI Sharon Ross NCI Mukesh Verma NCI Hemin Chin NEI Elise Feingold NHGRI Mike Pazin NHGRI Weiniu Gan NHLBI Susan Old NHLBI Pothur Srinivas NHLBI Anna McCormick NIA Suzana Petanceska NIA Conrad Malia NIAID Nasrin Nabavi NIAID Ashley Xia NIAID William Sharrock NIAMS Guoying Liu NIBIB Roderic Pettigrew NIBIB Carol Kasten‐Sportes NICHD Lisa Freund NICHD Susan Taymans NICHD Mark Caulder NIDA Genevieve deAlmeida‐Morris NIDA Donna Jones NIDA Jonathan Pollock NIDA Dena Procaccini NIDA Joni Rutter NIDA Bracie Watson NIDCD Lillian Shum NIDCR Kristin Abraham NIDDK Olivier Blondel NIDDK Jessica Faupel‐Badger NIDDK Philip Smith NIDDK Julie Wallace NIDDK Lisa Chadwick NIEHS Gwen Collman NIEHS Christie Drew NIEHS Astrid Haugen NIEHS Jerry Heindel NIEHS Laurie Johnson NIEHS Kimberly McAllister NIEHS Srikanth Nadadur NIEHS Kristi Pettibone NIEHS Fred Tyson NIEHS Leroy Worth NIEHS Anthony Carter NIGMS Andrea Beckel‐Mitchener NIMH Michelle Freund NIMH Thomas Lehner NIMH Roger Little NIMH Aleksandra Vicentic NIMH Robert Riddle NINDS Randall Stewart NINDS Stephanie Courchesne OSC Patricia Labosky OSC Johanna Dwyer ODS Deborah 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 Epigenomics Novel Marks

NIH Roadmap Epigenomics Program

88 grants $230M

Epigenome Mapping Centers

GOAL: 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 types involved in disease Stamatoyannopoulos, Science 337:1190, 2012

Computational Epigenomics RFA (R01)

GOAL: Computational analyses taking advantage of the publicly available reference epigenomic maps along 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 Epigenomics Novel 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 toxins Asthma Cancer Insulin resistance Autoimmune Glaucoma Psychiatric Autism Substance 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 25 Nature 14 Science 4 Pubs Year

Lister et al. 2009 MethylC‐seq cited 1134 times Dena Procaccini

http://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
• f reference epigenomes (1000)
• Common data standards
• Rapid data sharing
• Understand epigenomic basis
• f disease
• @$125M non-US effort on

reference epigenomes, plus

IHEC Members: US: Roadmap Epigenomics European Union Canada Germany Japan South Korea US: ENCODE Singapore Italy United Kingdom Australia

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 neuronal epigenomes to interpret GWAS

Validation of animal epigenetic studies in post-mortem human brain

DeJager et al. 2014 Nat Neuro epub Lunnon 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?