AN INTRODUCTION TO EPIGENETICS DR CHLOE WONG

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1 AN INTRODUCTION TO EPIGENETICS DR CHLOE WONG MRC SGDP CENTRE, INSTITUTE OF PSYCHIATRY KING S COLLEGE LONDON Oct 2015

2 Lecture Overview WHY WHAT EPIGENETICS IN PSYCHIARTY

3 Technology-driven genomics research GENETIC DIVERSITY 2008-present

4 Very small effect sizes (OR < 1.2) Little replication and heterogeneity between studies Little information that will help with diagnosis, prediction of prognosis, or development of novel therapeutic strategies

5 Gene-environment interaction 5HTT SS individualsmore severe depressive symptoms 5HTT LL individualsless severe depressive symptoms 5

6 Molecular and Epidemiological Peculiarities Discordance of monozygotic twins Parental origin effects Peaks of susceptibility following major hormonal changes Fluctuating course of disease Paternal age effects Sexual dimorphism Periods of environmental sensitivity Age-dependent decline of symptoms Stability of prevalence rate despite reduced fecundity Non-mendelian inheritance: sporadic and familial cases

7 DNA Sequence Variation

8 Different species, not so different genome 50% 70% 90% 97% 98% 98 99%

9 Same genome, different cells

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11 The Historic and modern definitions of Epigenetics epi = on top of (Greek) The term 'epigenetics' was introduced by Conrad H. Waddington in 1942 to describe the interactions of genes with their environment that bring the phenotype into being.

12 The Historic and modern definitions of Epigenetics The current concept of epigenetics: the reversible regulation of gene expression mediated principally through changes in DNA methylation and chromatin structure, occurring independently of the DNA sequence Henikoff & Matzke

13 Genome(DNA) Environment Epigenome Phenotype

14 One genome...multiple epigenomes Same genotype many phenotypes!! All our cells contain the same DNA sequence but do very different things

15 Epigenetics: regulation of genomic activities Scenario A A simplistic view: Scenario B no epigenetic silencing significant expression Epigenetic modification Transcriptional silencing Altered gene expression complete epigenetic silencing no expression large amounts of protein Altered protein production no protein Phenotypic Change

16 Epigenetics: regulation of genomic activities Scenario A Scenario B no epigenetic silencing significant expression complete epigenetic silencing no expression large amounts of protein no protein

17 Epigenetics: regulation of genomic activities Scenario A Scenario B no epigenetic silencing significant expression complete epigenetic silencing no expression large amounts of protein no protein

18 Epigenetics: regulation of genomic activities Scenario A Scenario B no epigenetic silencing significant expression The DNA sequence determines what specific mrna molecules are synthesized complete epigenetic silencing no expression Epigenetics determines how much of the mrna large amounts is made, of protein and where and when it is no protein synthesized

19 Even genes that carry no disease predisposing sequence changes may be useless or harmful if not expressed in the appropriate amount, at the right time or in the right compartment of the cell

20 For example: Silencing (via hypermethylation) of tumor suppressor genes and DNA repair genes Global Hypomethylation expression of oncogenes, chromosome instability, and activation of retrotransposons

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22 Lecture Overview WHY WHAT EPIGENETICS IN PSYCHIARTY

23 Chromatin structure: from DNA to chromosome

24 DNA Methylation 5-Methyl-Cytosine: the 5 th DNA base (SAM) DNA methylation affects cytosines almost exclusively in the context CpG : i.e.cytosine-guanine

25 Functions of DNA methylation Transcriptional gene silencing X-chromosome inactivation (in females) Genomic imprinting Chromatin compaction Genome stability Suppression of homologous recombination between repeats Genome defense against retroviruses Genetic recombination & DNA mutability

26 Transcriptional gene silencing DNA methylation Displaces transcription factors & attracts methyl-binding proteins lead to gene expression

27 X Chromosome-Inactivation Mammalian sex chromosomes Female: XX Male: XY genes 2-2,500 genes Dosage compensation process: Adjusts genetic imbalance of X-linked genes in females via a process involving hypermethylation of CpG islands on the inactive X. Occurs randomly in early female embryonic development and is stable once established. Heterozygous females are thus mosaic for X-linked gene expression

28 Calico cat: coat colour is a product of random X-inactivation GENETIC CLONES!

29 Lecture Overview WHY WHAT EPIGENETICS IN PSYCHIARTY

30 The Dynamic Epigenome Genome can acquire / lose a methyl group much more readily than it can change its DNA sequence. The dynamic nature of epigenetic marks provides a mechanism by which an organism can respond to the environment without changing its hardware. Increasing evidence that epigenetic processes are highly sensitive to the environment, developmental factors, and stochastic events in the cell.

31 EPIGENOME

32 Epigenetics and Nutrition

33 Epigenetics and Nutrition

34 Epigenetics and Nutrition

35 Epigenetics and Nutrition

36 Dutch Winter Famine WWII Famine in winter German-occupied Netherlands 4.5 million people affected 667 kcal a day rations (1/3 of daily recommended intake for women and 1/4 for men)

37 PNAS (2008); 105(44) Prenatal exposed vs. unexposed sibling comparison of IGF2 methylation, 60 years later Periconceptional exposure was associated with a 5.2% lower methylation --- No effect seen in late gestational exposure Epigenetic information is particularly vulnerable in the early stages of pregnancy

38 Prenatal famine and schizophrenia 2x risk for schizophrenia Chinese Great Leap Forward Dutch Famine Susser et al (2008)

39 Epigenetics and Maternal Care Nature Neuroscience(2004); 7,

40 Epigenetics and Maternal Care

41 Epigenetics and Maternal Care Epigenetic patterns are reversible! Epigenetic destiny is not written in permanent ink

42 Epigenetics and Maternal Care Variations in maternal behaviour are associated with differences in oestrogen receptor Rat offspring of high licking/grooming mothers have higher methylation in the medial preoptic area than offspring of low licking/grooming mothers Cross-fostering confirmed an association between maternal care and oestrogen receptor expression Champagne et al (2006)

43 Are similar alterations seen in humans? I. Ouellet-Morin, C. C. Y. Wong, A. Danese, C.M. Pariante, A. S. Papadopoulos, J. Mill and L. Arseneault

44 Timing of environmental exposure is likely to be important Epigenome is particularly susceptible to deregulation during: Gestation Neonatal development Puberty / adolescence Old age Most vulnerable in embryogenesis DNA synthesis rate is high Time when elaborate DNA methylation patterns and chromatin structure required for normal tissue development are established

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46 2012 Significant associations between maternal smoking in pregnancy, assessed by plasma cotinine levels and methylation in cord blood at 26 CpGs (mapped to 10 genes).

47 Epigenetic factors play a major role in phenotypic outcome between genetically identical organisms Inbred Mice Cloned cat Cloned mice

48 DNA Methylation Histone H4 acetylation Histone H3 acetylation

49 DRD4 SERT MAOA

50 Discordant Monozygotic Twins an optimal resource for epigenetic studies of complex disease

51 ASD MZ Twin Study Molecular Psychiatry (2013) Mol Psy 2014 P<2.2E 16 (P<2.2E 16) Distinctive patterns of DNA methylation associated with both autism diagnosis and related behaviour traits, and increasing severity of symptoms

52 MZ Twin Study (TEDS) Unique Environmental Effect ASD Epigenetics Familial Effect, Ascertain time of manifestation High-risk baby sib study (BASIS) Multi-omics Case Control Post-mortem brain tissues (ATP, London, Oxford)

53 Biol Psych 2014

54 Epigenome is complex. Environment EPIGENOME Genetic variation Stochastic Events

55 Reference Epigenomes Technology Development Novel Epigenetic Marks Epigenomics of Human Health & Disease Neurodegeneration Bipolar disorder Schizophrenia Autism Atherosclerosis Hypertension SLE Kidney disease Asthma Insulin Resistence

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