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Epigenetics and the brain; the nature of nurture?

Epigenetics and the brain; the nature of nurture?. Anthony Isles Behavioural Genetics Group Cardiff University. What is epigenetics?. “ The transmission and perpetuation of information through cell division that is not based on the sequence of the DNA ” (after Conrad H. Waddington c. 1942).

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Epigenetics and the brain; the nature of nurture?

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  1. Epigenetics and the brain; the nature of nurture? Anthony Isles Behavioural Genetics Group Cardiff University

  2. What is epigenetics? “The transmission and perpetuation of information through cell division that is not based on the sequence of the DNA”(after Conrad H. Waddington c. 1942)

  3. What is epigenetics? “The transmission and perpetuation of information through cell division that is not based on the sequence of the DNA”(after Conrad H. Waddington c. 1942) • Development and differentiation • Maintenance of cellular identity

  4. What is epigenetics? Regulation, timing and level of gene expression Undifferentiated parent cell

  5. XXXXXXXXXXX What is epigenetics? Regulation, timing and level of gene expression Liver cell XXXXXXXXXXX Undifferentiated parent cell

  6. XXXXXXXXXXX XXXXX XXXXX What is epigenetics? Regulation, timing and level of gene expression XXXXX XXXXX Liver cell Neural cell Undifferentiated parent cell

  7. XXXXXXXXXXX XXXXX XXXXX What is epigenetics? Regulation, timing and level of gene expression XXXXX XXXXX Differentiation Liver cell Neural cell Undifferentiated parent cell

  8. XXXXXXXXXXX XXXXXXXXXXX XXXXX XXXXX XXXXX XXXXX Neural cell Neural cell Liver cell What is epigenetics? Regulation, timing and level of gene expression Liver cell Maintenance of cellular identity

  9. Molecular Mechanisms • How is molecular control of gene expression exerted? • DNA code remains unchanged • Epigenetics are another layer of information laid on top of the DNA code • Two main mechanisms: • DNA methylation • Histone (chromatin) modification

  10. Molecular Mechanisms– DNA methylation • DNA sequence made up of 4 chemical bases; adenosine, guanine, tyrosine and cytosine (A,G,T,C) • One base, cytosine is epigenetically modified by DNA methylation • Encoded DNA information (i.e. ‘C’) remains the same • Epigenetic code has changed… • DNA methylation generally = suppression of gene activity

  11. Histones; proteins around which DNA is bound • Histones are the main component of chromatin • Chromatin compacts and provides stability and structure to the DNA Molecular Mechanisms– histone modifications

  12. Molecular Mechanisms– histone modifications • Modifications of residues in the histone ‘tails’ • >40 possible modifications • Modification alter 3-D structure and make DNA more, or less, accessible • Acetylation found in regions of increased gene expression

  13. Molecular Mechanisms– histone modifications • Modifications of residues in the histone ‘tails’ • >40 possible modifications • Modification alter 3-D structure and make DNA more, or less, accessible • Acetylation found in regions of increased gene expression DNA-methylation and chromatin interact – differential recruitment of histones

  14. The relevance of epigenetics to brain function

  15. Epigenetic mechanisms and neurodevelopment disorders Epigenetics important in cell differentiation and maintenance Aberrant DNA-methylation (MECP2) • Rett syndrome • Rubinstein-Taybi syndrome • Angelman/Prader-Willi • Lack of Chromatin Binding Protein • Loss of Histone acetly-transferase • Mutations in tightly regulated genes • Paternally/maternally imprinted genes on 15q11-q13 • Also caused by loss of epigenetic control mechanism (i.e. no DNA loss)

  16. Environment and epigenetics The transmission and perpetuation of information through meiosis and/or mitosis that is not based on the sequence of the DNA (after Conrad H. Waddington c. 1942)

  17. Environment and epigenetics The transmission and perpetuation of information through meiosis and/or mitosis that is not based on the sequence of the DNA (after Conrad H. Waddington c. 1942) “…complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons.” Tsankova, Renthal, Kumar & Nestler2007 Nature Neuroscience Reviews 8: 355-367

  18. Environment and epigenetics- encoding life events • Identical twins have identical DNA • Global differences in epigenetic status between twins increases with age • Increased differences in methlyation • Green: areas of hypermethlyation • Red: areas hypomethylation • Yellow: equal levels of methylation Fraga et al. (2005) PNAS 102, 10604-10609

  19. Environment and epigenetics- encoding life events • Identical twins have identical DNA • Global differences in epigenetic status between twins increases with age • Increased differences in methlyation • Green: areas of hypermethlyation • Red: areas hypomethylation • Yellow: equal levels of methylation Different life events give rise to different patterns of epigenetic marks Fraga et al. (2005) PNAS 102, 10604-10609

  20. Environment and epigenetics- programming of by early life events • Female rats show varying levels of maternal care • Characterised by levels of licking and grooming of the pups • Maternal care previously has long term non-genomic, effects on the offspring • Altered reactivity to stress • Altered expression of hippocampal GR • High licking and grooming in mother leads to high licking and grooming in offspring (and vice versa) Nature neuroscience 2004 7:847-54

  21. Environment and epigenetics- programming of by early life events • Altered DNA methylation • Altered recruitment of histones Nature neuroscience 2004 7:847-54

  22. Childhood abuse leads to long term altered expression of Glucorticoid receptor (GR) expression Environment and epigenetics- programming of by early life events McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)

  23. Childhood abuse leads to long term altered expression of Glucorticoid receptor (GR) expression • Corresponding changes in methylation of the neuron specific GR promoter, NR3C1 Environment and epigenetics- programming of by early life events McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)

  24. Environment and epigenetics- where genes and environment meet • Genome variation can effect gene function in several ways • Changes in encoded product (amino acid sequence) • Changes in regulatory regions that effect expression

  25. Environment and epigenetics- where genes and environment meet • Genome variation can effect gene function in several ways • Changes in encoded product (amino acid sequence) • Changes in regulatory regions that effect expression • Epigenetics influence gene expression • Epigenetic change may interact with genetic variation • Provides the molecular link between genes and environment…

  26. Science (2003) 301: 386-389 Science (2002) 297: 851-854 PNAS (2004) 101: 17316-17321 Arch Gen Psychiatry (2004) 61:738-44 Biol. Psych. 18 (2006) 59: 673-680 Environment and epigenetics- where genes and environment meet Low expressing MAO-A gene variant interacts with childhood maltreatment Effects of 5-HTT gene variant on depression moderated by care

  27. Molecular Mechanisms– DNA methylation • DNA methylation usually correlates with decreased gene expression • Generally occurs in regulatory regions of genes - promoters and enhancers - not in the coding regions               Methylation of the reelin promoter in Schizophrenia Grayson D. R. et.al. PNAS 2005;102:9341-9346

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