Epigenetic Embedding of Early Life Experiences               Michael S. Kobor             Associate ProfessorCentre for Mo...
Understanding Epigenetics – a Journey Through Life         Epigenetics refers to persistent and heritable         alterati...
From Genome to Epigenomes –                Cellular Differentiation>25000 GenesIdentical Sequence1 Genome                P...
DNA Methylation, Chromatin, and Gene Regulation               Histone Modification               Chromatin Remodeling     ...
DNA Methylation, Chromatin, and Gene Regulation               Histone Modification               Chromatin Remodeling     ...
Maternal Diet Affects Epigenetic Gene       Regulation in Isogenic Offspring (Avy /a)         Young Mice                  ...
Impact of Epigenetics on Health and DiseaseNutrition and lifestyleof mother affectsepigenome of childMaternal care affects...
Integrative Model of Epigenetics              Epigenetics              Phenotypic               VariationGenetics         ...
Integrative Model of Epigenetics                  Epigenetics                   Phenotypic                    VariationGen...
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 2...
Presentation OutlineEpigenetics at the Interface of Genome and EnvironmentEpigenetic Variation in AdultsBiological Embeddi...
Early Life Experiences Getting Under the SkinEarly Life Socio-Economic Status             Early Life Parental Stress Level...
Biological Residue of Low Early-Life Social ClassChildhood      AdulthoodLow SES        Low SESLow SES        High SESHigh...
DNA Methylation Correlated with    Early Life Socio-Economic StatusEarly Life SES                   Current SES(Age 1-5)  ...
Maternal Warmth and Resilience of the Pro-Inflammatory Phenotype of Low Early-Life SES response to TLR2/6 stimulation     ...
Epigenetic Vestiges of Early Parental Adversity    Wisconsin Study of Families and Work (Longitudinal Birth Cohort)HCS: FD...
Maternal Stress During Infancy is                         Associated with DNA Methylation                     PGAM2 - cg23...
Gender-Specific Association of Maternal Stress                    During Infancy with DNA Methylation                     ...
Child-Centric Analysis of Wisconsin Family Data                                 Pre-School                                ...
Grade 1 and Epigenetic Imprint                                                Observed temperament; L9(PC;EL;LB) Anger sca...
Presentation OutlineEpigenetics at the Interface of Genome and EnvironmentEpigenetic Variation in AdultsBiological Embeddi...
Tissue-Specific DNA Methylation        Signatures in Human Brain and BloodPrincipal Componentsand Variance DistributionPC1...
Tissue-Specific DNA Methylation of the                       Gene Encoding Glucocorticoid Receptor          Full          ...
DNA Methylation Signatures of Aging           in Human Brain and BloodPC4: Age, Brain only        Principal component reco...
SummaryEpigenetics as an Integral Component of Human Health and DiseaseEpigenetic Variation in Adults       Tissue-Specifi...
Summary              EpigenomeExperiences                 Phenotypes              Tissue              Specificity         ...
AcknowledgementsCentre for Molecular Medicine and TherapeuticsDept. of Medical Genetics, CFRI, UBCLucia LamSarah NeumannSa...
Issues to ConsiderCorrelation versus CausalityRobustness of DNA Methylation in Response to EnvironmentsMalleability of Mar...
DNA Methylation and Gene Expression are  not Tightly Linked Across Individuals  Origin and consequences of variation of DN...
DNA Methylation is Predictive of          PBMC ex vivo Response.        Oligodeoxynucleotide               Lipopolysacchar...
Epigenetic Reflection of Pre-School                                                  Child Temperament                    ...
Epigenetic Trace of Kindergarten Temperament                            EDI-like measures (teacher report);               ...
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Epigenetics and Addiction Research - Michael Kobor

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This is a presentation that was given at the Lost in Translation 2013: Exploring the Origins of Addiction conference that took place on March 25 - 26, 2013 in Vancouver, British Columbia, Canada.

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Epigenetics and Addiction Research - Michael Kobor

  1. 1. Epigenetic Embedding of Early Life Experiences Michael S. Kobor Associate ProfessorCentre for Molecular Medicine and Therapeutics Child and Family Research Institute Department of Medical Genetics University of British Columbia www.cmmt.ubc.ca
  2. 2. Understanding Epigenetics – a Journey Through Life Epigenetics refers to persistent and heritable alterations in genome information that do NOT involve changes in DNA sequence Same Genome – Many Epigenomes Developmental Epigenome Programming Environmental Influences on Epigenome
  3. 3. From Genome to Epigenomes – Cellular Differentiation>25000 GenesIdentical Sequence1 Genome Persistent Programming Gene Expression Profiles >200 Cell Types >200 Epigenomes
  4. 4. DNA Methylation, Chromatin, and Gene Regulation Histone Modification Chromatin Remodeling Histone Variants RNA-Based Mechanisms DNA Methylation “Epigenetic” Regulation of Gene Expression (Reversible!) Active Gene Silent Gene -> mRNA made -> no mRNA made Unmethylated promoter DNA Methylated promoter DNA (CpG Islands) (CpG Islands) Methylated genic DNA Unmethylated genic DNA Acetylated Histones Deacetylated histones Histone H3 K4 methylation Histone H3 K9 methylation Histone variant H3.3 Canonical histone H3
  5. 5. DNA Methylation, Chromatin, and Gene Regulation Histone Modification Chromatin Remodeling Histone Variants RNA-Based Mechanisms DNA Methylation “Epigenetic” Regulation of Gene Expression (Reversible!) Active Gene Silent Gene -> mRNA made -> no mRNA made Unmethylated promoter DNA Methylated promoter DNA (CpG Islands) (CpG Islands) Methylated genic DNA Unmethylated genic DNA Acetylated Histones Deacetylated histones Histone H3 K4 methylation Histone H3 K9 methylation Histone variant H3.3 Canonical histone H3
  6. 6. Maternal Diet Affects Epigenetic Gene Regulation in Isogenic Offspring (Avy /a) Young Mice Adult Mice Obese LeanLow High Avy DNA MethylationHigh Low Avy ExpressionLow High Maternal Methyl Randy Jirtle Duke Waterland MCB 2003
  7. 7. Impact of Epigenetics on Health and DiseaseNutrition and lifestyleof mother affectsepigenome of childMaternal care affects epigenomeof offspringIdentical twins acquire discordantepigenomes during life-course
  8. 8. Integrative Model of Epigenetics Epigenetics Phenotypic VariationGenetics Environment
  9. 9. Integrative Model of Epigenetics Epigenetics Phenotypic VariationGenetics Environment Do individuals vary in their DNA methylation pattern?
  10. 10. Extensive Epigenetic Variation in Human Tissues What is DNA methylation associated with?
  11. 11. Demographic and Psychosocial Factors are Associated with DNA methylation. Lam et al PNAS 2012
  12. 12. Presentation OutlineEpigenetics at the Interface of Genome and EnvironmentEpigenetic Variation in AdultsBiological Embedding of Early Life Experiences Gene Expression and Pro-Inflammatory Phenotype Epigenetic Vestiges of Family Environment Epigenetic Reflections of Childhood TemperamentTurning Challenges into Opportunities – Peripheral versus Central
  13. 13. Early Life Experiences Getting Under the SkinEarly Life Socio-Economic Status Early Life Parental Stress Level 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)
  14. 14. Biological Residue of Low Early-Life Social ClassChildhood AdulthoodLow SES Low SESLow SES High SESHigh SES Low SESHigh SES High SES Miller et al PNAS 2009
  15. 15. DNA Methylation Correlated with Early Life Socio-Economic StatusEarly Life SES Current SES(Age 1-5) (Age 30-40) Lam et al PNAS 2012
  16. 16. Maternal Warmth and Resilience of the Pro-Inflammatory Phenotype of Low Early-Life SES response to TLR2/6 stimulation 10000 800 response to TLR9 stimulation IL-6 production (pg/ml) in IL-6 production (pg/ml) in 8000 600 6000 400 4000 200 2000 0 0 Low High Low High Maternal Warmth Maternal Warmth Chen et al Mol Psychiatry 2010 Choose your parents wisely….
  17. 17. Epigenetic Vestiges of Early Parental Adversity Wisconsin Study of Families and Work (Longitudinal Birth Cohort)HCS: FDR <5% Full Group Girls BoysMCS: FDR 5%-20% (n=109) (n=60) (n=49) Maternal Stress 139 HCS 1 HCS 3 HCSInfancy Paternal Stress 3 HCS Maternal StressPreschool Paternal Stress 3 HCS 6/9 HCS 29 MCS 314/1057 MCS Essex et al Child Development 2011
  18. 18. Maternal Stress During Infancy is Associated with DNA Methylation PGAM2 - cg23616741[P] PGAM2 - cg26057752[C] 0.6 0.4 0.5 0.3 avg beta avg beta 0.4 0.2 0.3 0.1 0.2 0.2 0.4 0.6 0.8 0.2 0.4 0.6 0.8 log(maternal stress at infancy) log(maternal stress at infancy)In the set of 37 high confidence sites associated with maternal stress at infancy andhaving 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%) Essex et al Child Development 2011
  19. 19. Gender-Specific Association of Maternal Stress During Infancy with DNA Methylation Associated CpG site in Female-specific full group and boys PKN1 associated CpG site C5orf21 0.9 0.9Average beta beta 0.8 0.8 Averagebeta avg beta avg 0.7 0.7 0.6 0.6 PKN1 rho=0.40 Δ6.4% q=0% C5orf21 rho=0.50 Δ10.6% q=0% rho=0.50 Δ7.5% q=0% 0.2 0.4 0.6 0.8 0.2 0.4 0.6 0.8 Maternal Stress Infancy maternal stress at infancy Maternal Stress Infancy maternal stress at infancy Is variation in DNA methylation associated with children’s behavior? Essex et al Child Development 2011
  20. 20. Child-Centric Analysis of Wisconsin Family Data Pre-School Kindergarten Grade 1
  21. 21. Grade 1 and Epigenetic Imprint Observed temperament; L9(PC;EL;LB) Anger scale l9@ans ↑246 (74) HCS 0.32 to 0.60 (0.32 to 0.48) 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 LRRC2 rho= 0.399 POLR3C rho= 0.415 PRSS21 rho= 0.343 SLC29A4 rho= 0.455 TDGF1 rho= 0.346 TRIM16 rho= 0.382 1.0 0.8 0.6 0.4 0.2 0.0 DLX5 rho= 0.35 DLX5 rho= 0.371 DLX5 rho= 0.389 DLX5 rho= 0.398 FLJ11017 rho= 0.326 FLJ20444 rho= 0.392 1.0bqNorm avgbeta 0.8 0.6 0.4 0.2 0.0 ALX4 rho= 0.404 C16orf30 rho= 0.408 C1orf188 rho= 0.442 C21orf56 rho= 0.323 C21orf56 rho= 0.368 CD24 rho= 0.447 1.0 0.8 0.6 0.4 0.2 0.0 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 l9ans Boyce et al, in preparation
  22. 22. Presentation OutlineEpigenetics at the Interface of Genome and EnvironmentEpigenetic Variation in AdultsBiological Embedding of Early Life ExperiencesTurning Challenges into Opportunities – Peripheral versus Central Korbinian Brodmann Areas 7: Parietal cortex 10: Frontal cortex 20: Temporal cortex Gustavo Turecki, McGill University Michael Meaney, McGill University Eldon Emberly, Simon Fraser University
  23. 23. Tissue-Specific DNA Methylation Signatures in Human Brain and BloodPrincipal Componentsand Variance DistributionPC1: Brain – Blood Farre et al, in preparation
  24. 24. Tissue-Specific DNA Methylation of the Gene Encoding Glucocorticoid Receptor Full Methylation PBMC Samples BRAIN No MethylationMeth450K Coord
  25. 25. DNA Methylation Signatures of Aging in Human Brain and BloodPC4: Age, Brain only Principal component reconstruction on anPC5: Age, Brain and Blood 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 Farre et al, in preparation
  26. 26. SummaryEpigenetics as an Integral Component of Human Health and DiseaseEpigenetic Variation in Adults Tissue-Specific Variation Associated with Many VariablesGenomic 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 MethylationPeripheral versus Central Tissues Complex Distinct and Overlapping Signatures
  27. 27. Summary EpigenomeExperiences Phenotypes Tissue Specificity Development Genome
  28. 28. AcknowledgementsCentre for Molecular Medicine and TherapeuticsDept. of Medical Genetics, CFRI, UBCLucia LamSarah NeumannSarah MahPau FarreEdith Chen University of British Columbia / Northwestern UniversityGreg Miller University of British Columbia / Northwestern UniversityW. Thomas Boyce University of British ColumbiaClyde Hertzman University of British ColumbiaMarilyn Essex University of WisconsinHunter Fraser Stanford UniversityEldon Emberly Simon Fraser UniversityGustavo Turecki McGill UniversityMichael Meaney McGill University Human Early Learning Partnership National Institutes of Health Canadian Institutes of Health Research Mowafaghian Foundation Canadian Institute for Advanced Research
  29. 29. Issues to ConsiderCorrelation versus CausalityRobustness of DNA Methylation in Response to EnvironmentsMalleability of Marks upon InterventionTissue Specificity – Peripheral versus CentralRelationship between DNA Methylation and Gene ExpressionInterplay between Genetics, Epigenetics and the EnvironmentApplication of Different Statistical ApproachesTurning Challenges into Opportunities: the Next 5 YearsEpigenetics – 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 SamplesBirth Cohorts, Environmental AssessmentsPredictive Epigenetic BiomarkersCausality: Model Organisms, Therapeutic InterventionExpanding Beyond DNA Methylation (non-coding RNAs, Histones)Drug Effects on Epigenome
  30. 30. DNA Methylation and Gene Expression are not Tightly Linked Across Individuals Origin and consequences of variation of DNA methylation Hypothesis: recalling history and/or priming future response Interaction with other epigenetic modifications Lam et al PNAS 2012
  31. 31. DNA Methylation is Predictive of PBMC ex vivo Response. Oligodeoxynucleotide Lipopolysaccharid TLR-9 agonist TLR-4 agonistVariation Correlated with:Demographic Factors, Biological Factors, Lifestyle, Immune Response,Early Life Experiences, and Genetics Lam et al PNAS 2012
  32. 32. Epigenetic Reflection of Pre-School Child Temperament Anger component of Mother Reported "Childrens Behavior Questionnaire" 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) 3.5 4.0 4.5 5.0 5.5 6.0 6.5 3.5 4.0 4.5 5.0 5.5 6.0 6.5 3.5 4.0 4.5 5.0 5.5 6.0 6.5 KLF2 rho= 0.361 LIX1 rho= 0.362 LOC126208 rho= 0.379 LR8 rho= 0.339 PDE2A rho= 0.324 SLC25A21 rho= 0.34 ZNF496 rho= 0.348 0.6 0.4bqNorm avgbeta 0.2 0.0 ACTN2 rho= 0.395 ACTR3 rho= 0.325 C18orf22 rho= 0.33 DPYSL4 rho= 0.337 ELOVL6 rho= 0.339 HSD11B2 rho= 0.324 IGSF4 rho= 0.324 0.6 0.4 0.2 0.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 3.5 4.0 4.5 5.0 5.5 6.0 6.5 3.5 4.0 4.5 5.0 5.5 6.0 6.5 3.5 4.0 4.5 5.0 5.5 6.0 6.5 m67cbep Boyce et al, in preparation
  33. 33. Epigenetic Trace of Kindergarten Temperament EDI-like measures (teacher report); ZMYND12 rho= -0.325 TT8 Health and Behavior Questionnaire EXT (ODD;CD;OAG) inverse 0.8 0.6 INVtt8@8ex 0.4 ↓201(31) HCS -0.26 to -0.44 (-0.26 to -0.44) 0.2 0.0 RB1 rho= -0.276 TCP10 rho= -0.33 TRIM15 rho= -0.28 TRIM16 rho= -0.298 TRIM36 rho= -0.302 TSGA13 rho= -0.262 0.8 0.6 0.4 0.2 0.0 MRGPRX1 rho= -0.359 NALP12 rho= -0.274 NPDC1 rho= -0.267 NR1I2 rho= -0.323 PRDM14 rho= -0.283 PRTN3 rho= -0.276 0.8 0.6bqNorm avgbeta 0.4 0.2 0.0 GNAS rho= -0.265 IGF2AS rho= -0.396 KBTBD7 rho= -0.438 LRRFIP1 rho= -0.357 MGST1 rho= -0.275 MRGPRF rho= -0.274 0.8 0.6 0.4 0.2 0.0 DLX5 rho= -0.268 DLX5 rho= -0.27 DLX5 rho= -0.312 ELAVL4 rho= -0.265 FIP1L1 rho= -0.291 GIMAP1 rho= -0.276 0.8 0.6 0.4 0.2 0.0 AMT rho= -0.27 C10orf89 rho= -0.262 C6orf25 rho= -0.28 CARD8 rho= -0.279 CHD1L rho= -0.295 DLX5 rho= -0.263 0.8 0.6 0.4 0.2 0.0 0.5 0.6 0.7 0.8 0.9 1.0 0.5 0.6 0.7 0.8 0.9 1.0 0.5 0.6 0.7 0.8 0.9 1.0 INVtt88ex Boyce et al, in preparation

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