Epigenetics and Addiction Research - Michael Kobor
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Transcript of Epigenetics and Addiction Research - Michael Kobor
www.cmmt.ubc.ca
Epigenetic Embedding of Early Life Experiences
Michael S. Kobor Associate Professor
Centre for Molecular Medicine and Therapeutics Child and Family Research Institute
Department of Medical Genetics University of British Columbia
Understanding Epigenetics – a Journey Through Life
Developmental Epigenome Programming Environmental Influences on Epigenome
Same Genome – Many Epigenomes
Epigenetics refers to persistent and heritable alterations in genome information that do NOT involve changes in DNA sequence
From Genome to Epigenomes – Cellular Differentiation
>25000 Genes Identical Sequence 1 Genome
>200 Cell Types >200 Epigenomes
Persistent Programming Gene Expression Profiles
Active Gene -> mRNA made
“Epigenetic” Regulation of Gene Expression (Reversible!)
DNA Methylation, Chromatin, and Gene Regulation
Silent Gene -> no mRNA made
Unmethylated promoter DNA (CpG Islands) Methylated genic DNA Acetylated Histones Histone H3 K4 methylation Histone variant H3.3
Methylated promoter DNA (CpG Islands) Unmethylated genic DNA Deacetylated histones Histone H3 K9 methylation Canonical histone H3
Histone Modification Chromatin Remodeling Histone Variants RNA-Based Mechanisms DNA Methylation
Active Gene -> mRNA made
“Epigenetic” Regulation of Gene Expression (Reversible!)
DNA Methylation, Chromatin, and Gene Regulation
Silent Gene -> no mRNA made
Unmethylated promoter DNA (CpG Islands) Methylated genic DNA Acetylated Histones Histone H3 K4 methylation Histone variant H3.3
Methylated promoter DNA (CpG Islands) Unmethylated genic DNA Deacetylated histones Histone H3 K9 methylation Canonical histone H3
Histone Modification Chromatin Remodeling Histone Variants RNA-Based Mechanisms DNA Methylation
Maternal Diet Affects Epigenetic Gene Regulation in Isogenic Offspring (Avy /a)
Avy Expression
Avy DNA Methylation
High
High Low
Low
Maternal Methyl
High Low
Randy Jirtle Duke Waterland MCB 2003
Young Mice Adult Mice
Obese Lean
Nutrition and lifestyle of mother affects epigenome of child
Impact of Epigenetics on Health and Disease
Identical twins acquire discordant epigenomes during life-course
Maternal care affects epigenome of offspring
Environment
Epigenetics
Genetics
Phenotypic Variation
Integrative Model of Epigenetics
Environment
Epigenetics
Genetics
Phenotypic Variation
Integrative Model of Epigenetics
Do individuals vary in their DNA methylation pattern?
Extensive Epigenetic Variation in Human Tissues
What is DNA methylation associated with?
Demographic and Psychosocial Factors are Associated with DNA methylation.
Lam et al PNAS 2012
Epigenetics at the Interface of Genome and Environment Epigenetic Variation in Adults Biological Embedding of Early Life Experiences
Gene Expression and Pro-Inflammatory Phenotype Epigenetic Vestiges of Family Environment Epigenetic Reflections of Childhood Temperament
Turning Challenges into Opportunities – Peripheral versus Central
Presentation Outline
Early Life Socio-Economic Status Early Life Parental Stress Level
Early Life Experiences Getting Under the Skin
Childhood Temperament, Behavior, and Trajectories
Gregory Miller, Edith Chen (Psychology, UBC / Northwestern) W. Thomas Boyce (Human Early Learning Partnership, UBC) Clyde Hertzman (Human Early Learning Partnership, UBC) Marilyn Essex (University of Wisconsin)
Childhood Adulthood
Low SES Low SES High SES High SES
Low SES High SES Low SES High SES
Biological Residue of Low Early-Life Social Class
Miller et al PNAS 2009
DNA Methylation Correlated with Early Life Socio-Economic Status
Early Life SES (Age 1-5)
Current SES (Age 30-40)
Lam et al PNAS 2012
Maternal Warmth and Resilience of the Pro- Inflammatory Phenotype of Low Early-Life SES
0
2000
4000
6000
8000
10000
Low High
Maternal Warmth
IL-6
pro
duct
ion
(pg/
ml)
in
resp
onse
to T
LR2/
6 st
imul
atio
n
0
200
400
600
800
Low High
Maternal Warmth
IL-6
pro
duct
ion
(pg/
ml)
in
resp
onse
to T
LR9
stim
ulat
ion
Choose your parents wisely…. Chen et al Mol Psychiatry 2010
Paternal Stress
Paternal Stress
Maternal Stress
Maternal Stress Infancy
Preschool
Full Group (n=109)
Girls (n=60)
Boys (n=49)
139 HCS
HCS: FDR <5% MCS: FDR 5%-20%
1 HCS
3 HCS
3 HCS
3 HCS 29 MCS
6/9 HCS 314/1057 MCS
Epigenetic Vestiges of Early Parental Adversity Wisconsin Study of Families and Work (Longitudinal Birth Cohort)
Essex et al Child Development 2011
In the set of 37 high confidence sites associated with maternal stress at infancy and having more than 5% change in DNA, two CpG loci belonged to the same gene, PGAM2, which encodes phosphoglycerate mutase 2. cg26057752 CpG site (rho = .31, 9.6% DNA methylation change, FDR = 0%) cg23616741 CpG site (rho = .25, 10.4% DNA methylation change, FDR = 0%)
PGAM2 - cg23616741[P]
log(maternal stress at infancy)
avg
beta
0.2
0.3
0.4
0.5
0.6
0.2 0.4 0.6 0.8
PGAM2 - cg26057752[C]
log(maternal stress at infancy)
avg
beta
0.1
0.2
0.3
0.4
0.2 0.4 0.6 0.8
Maternal Stress During Infancy is Associated with DNA Methylation
Essex et al Child Development 2011
PKN1
maternal stress at infancy
avg
beta
0.6
0.7
0.8
0.9
0.2 0.4 0.6 0.8
C5orf21
maternal stress at infancy
avg
beta
0.6
0.7
0.8
0.9
0.2 0.4 0.6 0.8
Gender-Specific Association of Maternal Stress During Infancy with DNA Methylation
PKN1 rho=0.40 Δ6.4% q=0% rho=0.50 Δ7.5% q=0%
Maternal Stress Infancy Maternal Stress Infancy
Aver
age
beta
Aver
age
beta
C5orf21 rho=0.50 Δ10.6% q=0%
Associated CpG site in full group and boys
Female-specific associated CpG site
Essex et al Child Development 2011
Is variation in DNA methylation associated with children’s behavior?
Child-Centric Analysis of Wisconsin Family Data
Pre-School
Kindergarten
Grade 1
l9ans
bqN
orm
avg
beta
0.0
0.2
0.4
0.6
0.8
1.0
1 2 3 4 5 6 7
ALX4 rho= 0.404 C16orf30 rho= 0.408
1 2 3 4 5 6 7
C1orf188 rho= 0.442 C21orf56 rho= 0.323
1 2 3 4 5 6 7
C21orf56 rho= 0.368 CD24 rho= 0.447
DLX5 rho= 0.35 DLX5 rho= 0.371 DLX5 rho= 0.389 DLX5 rho= 0.398 FLJ11017 rho= 0.326
0.0
0.2
0.4
0.6
0.8
1.0FLJ20444 rho= 0.392
0.0
0.2
0.4
0.6
0.8
1.0LRRC2 rho= 0.399
1 2 3 4 5 6 7
POLR3C rho= 0.415 PRSS21 rho= 0.343
1 2 3 4 5 6 7
SLC29A4 rho= 0.455 TDGF1 rho= 0.346
1 2 3 4 5 6 7
TRIM16 rho= 0.382
l9@ans ↑246 (74) HCS 0.32 to 0.60 (0.32 to 0.48)
Grade 1 and Epigenetic Imprint Observed temperament; L9(PC;EL;LB) Anger scale
Boyce et al, in preparation
20: Temporal cortex 10: Frontal cortex 7: Parietal cortex
Korbinian Brodmann Areas
Epigenetics at the Interface of Genome and Environment Epigenetic Variation in Adults Biological Embedding of Early Life Experiences
Turning Challenges into Opportunities – Peripheral versus Central
Presentation Outline
Gustavo Turecki, McGill University Michael Meaney, McGill University Eldon Emberly, Simon Fraser University
Tissue-Specific DNA Methylation Signatures in Human Brain and Blood
Farre et al, in preparation
Principal Components and Variance Distribution
PC1: Brain – Blood
Full Methylation
BR
AIN
P
BM
C
No Methylation
Meth450K Coord
Sam
ples
Tissue-Specific DNA Methylation of the Gene Encoding Glucocorticoid Receptor
PC4: Age, Brain only PC5: Age, Brain and Blood
Principal component reconstruction on an Independent dataset composed of blood Samples of 656 individuals: (A) PC4: correlation 0.104 with p-value: 0.526. (B) PC5: correlation 0.554 with p-value: 1.081E-51
DNA Methylation Signatures of Aging in Human Brain and Blood
Farre et al, in preparation
Summary
Epigenetics as an Integral Component of Human Health and Disease
Epigenetic Variation in Adults Tissue-Specific Variation Associated with Many Variables
Genomic Embedding of Early Life Experiences
Biological Residue of Early Life Poverty DNA Methylation Associated with Early Life Parental Stress Childhood Temperament is Correlated with DNA Methylation
Peripheral versus Central Tissues
Complex Distinct and Overlapping Signatures
Epigenome
Tissue Specificity
Experiences Phenotypes
Genome
Development
Summary
Centre for Molecular Medicine and Therapeutics Dept. of Medical Genetics, CFRI, UBC Lucia Lam Sarah Neumann Sarah Mah Pau Farre
Human Early Learning Partnership National Institutes of Health Canadian Institutes of Health Research Mowafaghian Foundation Canadian Institute for Advanced Research
Edith Chen University of British Columbia / Northwestern University Greg Miller University of British Columbia / Northwestern University W. Thomas Boyce University of British Columbia Clyde Hertzman University of British Columbia Marilyn Essex University of Wisconsin Hunter Fraser Stanford University Eldon Emberly Simon Fraser University Gustavo Turecki McGill University Michael Meaney McGill University
Acknowledgements
Issues to Consider Correlation versus Causality Robustness of DNA Methylation in Response to Environments Malleability of Marks upon Intervention Tissue Specificity – Peripheral versus Central Relationship between DNA Methylation and Gene Expression Interplay between Genetics, Epigenetics and the Environment Application of Different Statistical Approaches
Turning Challenges into Opportunities: the Next 5 Years Epigenetics – is it Part of “the Missing Heritability”? What is the Role of Epigenetics in Common Diseases? Does Epigenetic Serve as a Memory of the Past, Predicting Future Response? Disease-Oriented Cohorts, Longitudinal Patient Samples Birth Cohorts, Environmental Assessments Predictive Epigenetic Biomarkers Causality: Model Organisms, Therapeutic Intervention Expanding Beyond DNA Methylation (non-coding RNAs, Histones) Drug Effects on Epigenome
DNA Methylation and Gene Expression are not Tightly Linked Across Individuals
Lam et al PNAS 2012
Origin and consequences of variation of DNA methylation Hypothesis: recalling history and/or priming future response Interaction with other epigenetic modifications
Variation Correlated with: Demographic Factors, Biological Factors, Lifestyle, Immune Response, Early Life Experiences, and Genetics
Oligodeoxynucleotide TLR-9 agonist
Lipopolysaccharid TLR-4 agonist
DNA Methylation is Predictive of PBMC ex vivo Response.
Lam et al PNAS 2012
m67cbep
bqN
orm
avg
beta
0.0
0.2
0.4
0.6
3.5 4.0 4.5 5.0 5.5 6.0 6.5
ACTN2 rho= 0.395 ACTR3 rho= 0.325
3.5 4.0 4.5 5.0 5.5 6.0 6.5
C18orf22 rho= 0.33 DPYSL4 rho= 0.337
3.5 4.0 4.5 5.0 5.5 6.0 6.5
ELOVL6 rho= 0.339 HSD11B2 rho= 0.324
3.5 4.0 4.5 5.0 5.5 6.0 6.5
IGSF4 rho= 0.324
KLF2 rho= 0.361
3.5 4.0 4.5 5.0 5.5 6.0 6.5
LIX1 rho= 0.362 LOC126208 rho= 0.379
3.5 4.0 4.5 5.0 5.5 6.0 6.5
LR8 rho= 0.339 PDE2A rho= 0.324
3.5 4.0 4.5 5.0 5.5 6.0 6.5
SLC25A21 rho= 0.34
0.0
0.2
0.4
0.6
ZNF496 rho= 0.348
M67cb@an ↑8(2) HCS 0.36 to 0.39 (0.36 to 0.38) ↑26(7) MCS 0.30 to 0.35 (0.30 to 0.33)
Epigenetic Reflection of Pre-School Child Temperament
Anger component of Mother Reported "Children's Behavior Questionnaire"
Boyce et al, in preparation
INVtt88ex
bqN
orm
avg
beta
0.00.20.40.60.8
0.5 0.6 0.7 0.8 0.9 1.0
AMT rho= -0.27 C10orf89 rho= -0.262
0.5 0.6 0.7 0.8 0.9 1.0
C6orf25 rho= -0.28 CARD8 rho= -0.279
0.5 0.6 0.7 0.8 0.9 1.0
CHD1L rho= -0.295 DLX5 rho= -0.263
DLX5 rho= -0.268 DLX5 rho= -0.27 DLX5 rho= -0.312 ELAVL4 rho= -0.265 FIP1L1 rho= -0.291
0.00.20.40.60.8
GIMAP1 rho= -0.2760.00.20.40.60.8
GNAS rho= -0.265 IGF2AS rho= -0.396 KBTBD7 rho= -0.438 LRRFIP1 rho= -0.357 MGST1 rho= -0.275 MRGPRF rho= -0.274
MRGPRX1 rho= -0.359 NALP12 rho= -0.274 NPDC1 rho= -0.267 NR1I2 rho= -0.323 PRDM14 rho= -0.283
0.00.20.40.60.8
PRTN3 rho= -0.2760.00.20.40.60.8
RB1 rho= -0.276 TCP10 rho= -0.33 TRIM15 rho= -0.28 TRIM16 rho= -0.298 TRIM36 rho= -0.302 TSGA13 rho= -0.2620.00.20.40.60.8
ZMYND12 rho= -0.325
INVtt8@8ex ↓201(31) HCS -0.26 to -0.44 (-0.26 to -0.44)
Epigenetic Trace of Kindergarten Temperament EDI-like measures (teacher report); inverse TT8 Health and Behavior Questionnaire EXT (ODD;CD;OAG)
Boyce et al, in preparation