Learning in heredity and evolution: an epigenetic perspective ACBS, Eva Jablonka July 2013

1. Learning in heredity and evolution:  an epigenetic perspectiveACBS,Eva Jablonka July 2013

2. What is epigenetics, epigenetic inheritance and are epigenetic mechanisms? Psychiatric epigenetics; the epigenetics of learning Epigenetic transmission of acquired behavioral dispositions Some evolutionary implications (early evolution)

3. Epigenetics The science of enduring changes in the pattern of gene activity, during embryo development and beyond, that do not involve alteration of the DNA sequence. These changes occur in response to conditions within the embryo and more generally. (Mark Pemberey) Epigenetics is the study of developmental processes [in prokaryotes and eukaryotes] that lead to persistent, self-maintaining, changes in the states of organisms, the components of organisms, or the lineages of organisms (Jablonka and Lamb)

4. Different Cell Types with the Same DNA

5. Genetically identical

6. Endocrine system mediating temperature-dependent polyphenism: Bicyclus Low ecdysone High ecdysone

7. Predator-induced Polyphenism: Daphnia Miyakawa, H. et al . 2010. Gene up-regulation in response to kairomones in the waterflea Daphnia pulex. BMC Developmental Biology 10:45. Hox3, extradenticle and escargot

8. Epigenetic inheritance Epigenetic inheritance is a component of epigenetics. It occurs when phenotypic variations that do not stem from variations in DNA base sequence are transmitted to subsequent generations of cells or organisms. It is used in a broad and a narrow (cellular) sense.

9. Epigenetic inheritance Epigenetic inheritance is a component of epigenetics. It occurs when phenotypic variations that do not stem from variations in DNA base sequence are transmitted to subsequent generations of cells or organisms. It is used in a broad and a narrow (cellular) sense.

10. Cellular epigenetic inheritance • Cellular epigenetic inheritance is the transmission from mother cell to daughter cell of variations that are not the result of differences in DNA base sequence or the present environment. The cell is the unit of transmission. Transmission can be through • self-sustaining metabolic loops • self-reconstructing three-dimensional structures • chromatin marks • RNAs • It occurs during cell division in prokaryotes, mitotic cell division in the soma of eukaryotes, and sometimes during the meiotic divisions in the germline. Jablonka and Raz (2009) found over 100 studies of transgenerational cellular epigenetic inheritance. Many more studies were published since.

11. Chromatin variations

12. Figure 1: Mechanisms involved in chromatin modificationCatherine Dulac Nature 465:728–735, 2010doi:10.1038/nature09231

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

14. RNA silencing and its transmission

15. Disease-associated epigenetic changes inmonozygotic twins discordant for schizophreniaand bipolar disorderDempster et al 2011 Human Molecular Genetics, 2011, Vol. 20, No. 24 4786–4796 Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. . Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.

16. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traitsWong et al 2013, Molecular Psychiatry (2013), 1–9 We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

17. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse Patrick O McGowan, Aya Sasaki, Ana C D’Alessio, Sergiy Dymov, Benoit Labonte´, Moshe Szyf, Gustavo Turecki & Michael J Meaney Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls.We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A–inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

19. Fear Conditioning

20. Epigenetic changes in a rodent model of post-traumaticstress disorder (PTSD). (a) In Roth et al.,57 PTSD was modeled in rats using two unpredictable and inescapable exposures to a cat, in which the rat was enclosed in a plexiglass container while the cat circled above for 1 h. Effects of trauma were enhanced by social instability in the stressed animals, which consisted of changing the animal’s cagemate daily for all 31 days of the experiment while control animals had a stable cagemate throughout the experiment. (b) Bisulfite sequencing PCR demonstrated region-specific effects of stress on Bdnf at exon IV in the hippocampus. Increases in methylation were found in the dentate gyrus and CA1 of the dorsal hippocampus, whereas decreased methylation was found in CA3 of the ventral hippocampus

21. Trans-generational effects that by-pass the germ line (soma-soma, experience-dependent)

22. Trans-generational effects

23. Soma-to-soma Transmission: Maternal behaviour in the rat

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

25. Putative promoter sites of genomic GR GR GENE PUTATIVE PROMOTER SITES 11 14 15 16 17 18 19 110 111 2 1681 ccc 1741 ctctgctagt gtgacacactt1cg2cgcaactc3cgcagttgg4cggg5cg6cggaccacccctg7c 1801ggctctgc8cggctggctgtcaccct9cgggggctctggctgc10cgaccca11cgggg12cgggct 1861c13cgag14cggttccaagcct15cggagtggg16cggggg17cgggagggagcctggg agaa NGFI-A (McCormick J.A., Mol Endo. 2000)

26. Transgenerational Rescue of a Genetic Defect in Long-Term Potentiation and Memory Formation by Juvenile Enrichment Junko A. Arai, Shaomin Li, Dean M. Hartley, and Larry A. Feig …Here, we demonstrate that exposure of 15-d-old mice to 2 weeks of an enriched environment (EE), that includes exposure to novel objects, elevated social interactions and voluntary exercise, enhances long-term potentiation (LTP) not only in these enriched mice but also in their future offspring through early adolescence, even if the offspring never experience EE. In both generations, LTP induction is augmented by a newly appearing cAMP/p38 MAP kinase-dependent signaling cascade. Strikingly, defective LTP and contextual fear conditioning memory normally associated with ras-grf knock-out mice are both masked in the offspring of enriched mutant parents. The transgenerational transmission of this effect occurs from the enriched mother to her offspring during embryogenesis. If a similar phenomenon occurs in humans, the effectiveness of one’s memory during adolescence, particularly in those with defective cell signaling mechanisms that control memory, can be influenced by environmental stimulation experienced by one’s mother during her youth. Good system for testing for epigenetic inheritance

27. Gametic Epigenetic inheritance

28. Linaria Wild-type Epimutant

29. Germline transmission of vinclozolin-induced changes Jirtle and Skinner 2007

30. Vinclozolin treatment has trans-generational effects on mate preference April 2007, PNAS David Crews, Andrea C. Gore, Timothy S. Hsu, Nygerma L. Dangleben, Michael Spinetta, Timothy Schallert, Matthew D. Anway, and Michael K. Skinner Changes in the methylation pattern of many genes is involved. Heritable epigenetic changes are called epimutations.

31. Epigenetic Transmission of the Impact of Early Stress Across Generations BIOL PSYCHIATRY 2010;68:408–415 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 depressive-like 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.

32. 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

33. WIREs Cogn Sci 2013, 4:105–115. doi: 10.1002/wcs.1205

34. Human persistent pollution

35. Religious wars: chronic stress

36. Evolution

37. Learning and evolution The Baldwin effect: learning-adaptation first, genetic changes follow (stabilize, facilitate etc. the learnt response). Drives the evolution of learning itself including motivational, sensory and motor aspects of behavior in the focal species and in interacting species. Drives morphological adaptations (e.g. defenses) Leads to both increased canalization (buffering) and increased developmental plasticity. The evolutionary sophistication of learning and memory led to major transitions in animal evolution. Associative learning drove the Cambrian explosion The evolution of symbol based-learning (linguistic communication and representation) in hominins.

38. When did associative learning (AL) evolve? Why was it selected? what were the evolutionary effects?

39. Distribution of AL: all vertebrates and several groups of invertebrates

40. AL was the adaptability driver of the Cambrian explosion The evolution of AL led to ecological arms races, evolution of sensory modalities, learning etc. through the Baldwin effect. It led to ongoing stress (the smoke detector principle) and this enhanced generation of variations (until more efficient whole-organism stress responses evolved) Predictions: the bifurcation leading to nephrozoans was characterized by the appearance of new neural/learning-specific pfams and MiRs (preliminary results support this conjecture).

41. The evolution of lanaugage