What is Epigenetics? Eva Jablonka. Five Mothers by Anna Zeligowski

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1 What is Epigenetics? Eva Jablonka Five Mothers by Anna Zeligowski

2 Epigenetics the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being (Waddington 1968 p. 9; based on Waddington 1942).

3 Strands of epigenetic research since the 1950s: Developmental plasticity and canalization during development (Waddington) Trans-determination and cell memory (Hadorn) X-inactivation (Lyon) Metabolic loops in microorganisms (Nanney) Structural heredity in ciliates (Sonneborn) Non-Mendelian heredity in plants (Brink) Heredity in cells in culture (Harris) DNA methylation Holliday and Pugh (1975) Riggs (1975) Sager and Kitchin (1975) Imprinting (revived during the late 1980 s, mainly through studies of transgenes)

4 Different Cell Types with the Same DNA

5 Waddington s epigenetic landscape Waddington, The Strategy of the Genes, p 29 & 36, 1957

6 X inactivation

7 A common language: Epigenetics: the study, in both prokaryotes and eukaryotes, of the stochastic and inducible developmental processes that lead to autoactalytic changes in gene activities and organismal states, which persist in the absence of the original inducing input. Epigenetic inheritance is a component of epigenetics. It occurs when phenotypic variations (e.g. in gene expression or in the architecture of cellular complexes) that do not stem from variations in DNA base sequence are transmitted to subsequent generations of cells or organisms. It necessitates cell division

8 Epigenetic is a bridge between disciplines David Crews, 2008

9 Epigenetic inheritance: broad and narrow conceptions

10 There are different modes of inheritance between generations 1. Through DNA (cellular-germline) inheritance 2. Through epigenetic (cellular-germline) inheritance 3. Through reconstructing early development (soma-soma) 4. Through socially learnt behaviour and reconstruction of later development and ecology (soma-soma) 5. Through symbolic culture (e.g. language) (soma soma)

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12 epigenetic inheritance symbolic behavioural developmental culture niche cellular epigenetic genetic germ body gamete GENERATION X GENERATION X+1 GENERATION X+2 INHERITANCE PATHWAYS

13 Mechanisms of cell memory and cell heredity 1. Self-sustaining loops (e.g. in bacteria, in unicellular fungi) 2. Spatial templating (inheritance of architectural variants, e.g. prions in yeast) 3. DNA methylation and chromatin marking 4. RNA-mediated cell memory and heredity

14 Self-sustaining loop

15 Candida albicans: white and opaque morphs white opaqu e

16 Structural inheritance prion form normal protein Jablonka & Lamb Evolution in Four Dimensions 2005, p. 124

17 Inheritance of [PSI+] and psi - in yeast cells

18 Epigenetic mechanisms involved in chromatin modifications Catherine Dulac Nature 465: , 2010 doi: /nature09231

19 DNA Methylation is the addition of a methyl group (M) to the DNA base cytosine (C) in a CpG sequence.

20 Replication of two DNA methylation patterns Jablonka & Lamb Evolution in Four Dimensions 2005, p. 129

21 Dynamic changes of transposon methylation during development gametogenesis FERTILIZATION embryogenesis IMPLANTATION Germ cell precursor spermatozo a zygote Methylation level oocyt e embryo Primordial germ cell blastocyst placenta ERASURE De novo Sex-specific ERASURE De novo Lineage-specific

22 Dynamic changes of transposon methylation during development gametogenesis FERTILIZATION embryogenesis IMPLANTATION Germ cell precursor spermatozo a zygote Methylation level oocyt e embryo Primordial germ cell blastocyst placenta ERASURE De novo Sex-specific ERASURE De novo Lineage-specific PLURIPOTENCY! PLURIPOTENCY! Epigenetic relaxation coincident with pluripotency state

23 Sexual dimorphism in gametogenesis kinetics and epigenetic setting Male gametogenesis BIRTH Meiotic Recombination Precursor PGC 6.5dpc 8.5dpc PGC 12.5dpc ProSpg 13.5dp c ProSpg 18.5dp c SSC Spg Lepto Pachy Diplo Spermati d Sperm ERASURE ESTABLISHMENT MAINTENANCE METHYLATION Female gametogenesis Meiotic Recombination BIRTH Precursor PGC 6.5dpc 8.5dpc PGC 12.5dpc Lepto Pachy Diplo 13.5dp 18.5dp c c Ng Growing Growing 60um MII ERASURE HYPOMETHYLATION ESTABLISHMENT Late establishment of methylation in oocytes, transposons stay hypomethylated for most of the reproductive life Existence of life-long proliferative stem cells in the male germline

24 Germline transmission of induced changes Jirtle and Skinner 2007

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26 Epigenetic Transmission of the Impact of Early Stress Across Generations BIOL PSYCHIATRY 2010;68: Tamara B. Franklin, Holger Russig, Isabelle C. Weiss, Johannes Gräff, Natacha Linder, Aubin Michalon,Sandor Vizi, and Isabelle M. Mansuy Background: Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations. Methods: To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14. Results: We show that chronic and unpredictable maternal separation induces depressivelike behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression. Conclusions: These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.

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28 Methylation of the CpG island surrounding the transcription initiation site of MeCP2 and CB1 genes was increased in F1 MSUS sperm (Figure 5A, 5C, 5E, 5G). In contrast, for the CRFR2 gene, methylation in a stretch of the CpG island located 5= of the transcription initiation site was decreased (Figure 5I and K). Methylation was not changed in target regions of the 5-HT1A or MAOA gene (Supplement 1, Figure S4). These data indicate that DNA methylation is altered in both directions and in a gene-specific manner in the germline of males subjected to early stress. Because they are present in the germline, the changes in DNA methylation could potentially be maintained and transmitted to the following generation. To test this hypothesis, we checked the profile of DNA methylation of the candidate genes in the brain of the female F2 progeny. Strikingly, a similar hypermethylation of the same stretch of CpGs was observed in both the MeCP2 and CB1 genes (Figure 5D and 5H) and a hypomethylation of CRFR2 CpG island (Figure 5L). These changes in methylation were functionally relevant because they were associated with a decrease in the level of mrna expression of these genes (Figure 5B, 5F, 5J). Cannabinoid receptor-1 (CB1), associated with emotionality in rodents; corticotrophinreleasing factor receptor 2 (CRFR2), a stress hormone receptor; MeCP2 control of stress, Rett syndrome. MAOA role in depression, and an enzyme that catalyzes the degradation of serotonin

29 RNA-mediated transmission of gene silencing

30 Inherited cardiac hypertrophy induced by injection of early embryos with a specific microrna Sections of the ventricular walls Wagner at al. Developmental Cell 14, 962, 2008

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32 Cases of trans-generational epigenetic inheritance Jablonka and Raz(Quarterly Review of Biology 2009) surveyed the literature on transgenerational cellular epigenetic inheritance and found*: 12 cases of epigenetic inheritance in bacteria 8 cases of epigenetic inheritance in protists, mostly in ciliates where a large number of loci and traits have been studied 19 cases in fungi, involving many phenotypes and loci 38 cases in plants, involving many loci and many traits; often they were induced by genomic stresses; *many more!!!! 27 cases in animals, some involving many loci; stress sometimes induced multiple epigenetic changes *many more cases since!!!

33 New studies: epigenetic variations in experimental and natural populations Experimental and natural populations of Arabidopsis, intra and interspecfic hybrids Dandelions: experimental and natural populations Marsh Orchid hybrids Spartina hybrids Mimulus natural populations Drosophila natural and experimental populations Schistosoma mansoni (trematode) Nectar yeast (heritable?) Guppies? (Additional studies in mangroves, tobacco, violets, mice, humans)

34 1. Through DNA (cellular-germline) inheritance 2. Through epigenetic cellular (germline) inheritance 3. Through reconstructing early development (soma-soma) 4. Through socially learnt behaviour and reconstruction of later development and ecology (soma-soma) 5. Through symbolic culture (e.g. language) (soma soma)

35 Induction and soma-to-soma inheritance of phenotypic variation

36 Mother field crickets Forewarn Offspring about Predators: A Trans-generational Maternal Effect on Behavior

37 Coprophagy

38 Food preferences in European rabbits

39 Food preferences in humans

40 There were 166 fathers who started smoking before age 11, and Pembrey found that these fathers sons were on average heavier than sons of fathers who took up this habit later in life or who never smoked. Daughters were unaffected.

41 Hormonally mediated inheritance of acquired characteristics in Mongolian gerbils Mongolian Gerbils

42 Maternal behaviour in the rat

43 Environmental programming of gene activity Glucocorticoid receptor gene PUP (Day 1-6) LOW LG GR GENE HIGH LG GR GENE ADULT (Day 90) GR RECEPTORS GR RECEPTORS STRESS RESPONSE STRESS RESPONSE

44 Putative promoter sites of genomic GR GR GENE PUTATIVE PROMOTER SITES ccc 1741 ctctgctagt gtgacacact t 1 cg 2 cgcaact c 3 cgcagttgg 4 cggg 5 cg 6 cgga ccacccctg 7 c 1801 ggctctgc 8 cg gctggctgtc accct 9 cgggg gctctggctg c 10 cgaccca 11 cg ggg 12 cgggct 1861 c 13 cgag 14 cggtt ccaagcct 15 cg gagtggg NGFI-A 16 cg gggg 17 cgggag ggagcctggg agaa (McCormick J.A., Mol Endo. 2000)

45 Social observational learning

46 Social learning in rats (Terkel and Aisner)

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50 We need the E4D perspective because the developmental conception of heredity has implication for : The study of heredity The study of evolution Medicine Agriculture