Identical Twins with Different Hair Color

1. Identical Twins with Different Hair Color

2. What is Epigenetics? • C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. • How do different adult stem cells know their fate? • Myoblasts can only form muscle cells • Keratinocytes only form skin cells • Hematopoetic cells only become blood cells • But all have identical DNA sequences. • Modern definition is non-sequence dependent inheritance. • How can identical twins have different natural hair colors? • How can a single individual have two different eye colors?

3. Mosaicism:An Individual with Two Different Eye Colors “Diego”

4. Mosaicism:An Individual Eye with Two Colors

5. What is Epigenetics? • C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. • How do different adult stem cells know their fate? • Myoblasts can only form muscle cells • Keratinocytes only form skin cells • Hematopoetic cells only become blood cells • But all have identical DNA sequences • Modern definition is non-sequence dependent inheritance. • How can identical twins have different natural hair colors? • How can a single individual have two different eye colors? • How can identical twin liter mates show different coat colors?

6. Coat Colors of Genetically Identical Agouti Mice Liter Mates

7. What is Epigenetics? • C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. • How do different adult stem cells know their fate? • Myoblasts can only form muscle cells • Keratinocytes only form skin cells • Hematopoetic cells only become blood cells • But all have identical DNA sequences. • Modern definition is non-sequence dependent inheritance. • How can identical twins have different natural hair colors? • How can a single individual have two different eye colors? • How can identical twin liter mates show different coat colors? • How can just paternal or maternal traits be expressed in offspring? This is called genetic imprinting. • How can females express only one X chromosome per cell? • How can acquired traits be passed on to offspring? • Some changes in gene expression that are, in fact, heritable!

8. DNA Methylation & the Epigenetic Code Paula Vertino, Henry Stewart Talks

9. DNA Methylation & Histone ModificationsForm the Epigenetic Code Paula Vertino, Henry Stewart Talks

10. Methylation of Cytosine in DNA Paula Vertino, Henry Stewart Talks

11. 5-Methyl Cytosine in DNA Paula Vertino, Henry Stewart Talks

12. Cytosine Methylation MaintainsInactive-Condensed Chromatin State Transcription factors RNA polymerase Transcription Acetylation 5-methyl-C DNA methyltransferase Methyl-CpG Binding proteins and associated co-repressors Histone deacetylase Transcription blocked Deacetylation X Chromatin compaction Transcriptional silencing Alex Meissner, Henry Stewart Talks

13. 5-Methyl Cytosine is Found in Heterochromatic Regions John Greally, Henry Stewart Talks

14. Structure & Epigenetics ofEuchromatin versus Heterochromatin Me Paula Vertino, Henry Stewart Talks

15. Maintenance ofCytosine Methylation Alex Meissner, Henry Stewart Talks Alex Meissner, Henry Stewart Talks

16. Passive Demethylation of5-Methyl-Cytosine Alex Meissner, Henry Stewart Talks Alex Meissner, Henry Stewart Talks

17. Establishment and Maintenance ofCytosine Methylation Alex Meissner, Henry Stewart Talks

18. Some DNA Methyl Transferases are Essential Alex Meissner, Henry Stewart Talks

19. Some DNA Methyl Transferases are Essential Alex Meissner, Henry Stewart Talks

20. Methylated DNA from Zygote to Adult Alex Meissner, Henry Stewart Talks

21. DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks

22. DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks

23. Critical CpG Sequences inCpG Islands Near Promoters Alex Meissner, Henry Stewart Talks

24. Organization of the Epigenome Paula Vertino, Henry Stewart Talks

25. Epigenetic Imprinting Marisa Bartolomei, Henry Stewart Talks

26. Methylation Changes During Development Marisa Bartolomei, Henry Stewart Talks

27. Demethylation of the Paternal Genome Adrien Bird, Henry Stewart Talks

28. Methylation Changes During Development Paula Vertino, Henry Stewart Talks

29. Methylation Changes During Development Paula Vertino, Henry Stewart Talks

30. Methylation Changes During Development Paula Vertino, Henry Stewart Talks

31. X Chromosome Inactivation:Barr Bodies Barr, M. L., Bertram, E. G., (1949), A Morphological Distinction between Neurones of the Male and Female, and the Behaviour of the Nucleolar Satellite. Nature. 163 (4148): 676-7. Lyon, M. F., (2003), The Lyon and the LINE hypothesis. j.semcdb 14, 313-318. (Abstract)

32. X Chromosome Inactivation:CG Island Methylation Adrien Bird, Henry Stewart Talks

33. Only one X is active Barbara Migeon, Henry Stewart Talks

34. Inactive X has unacetylated histone H4 Barbara Migeon, Henry Stewart Talks

35. Agouti Genes in Mice Emma Whitelaw, Henry Stewart Talks

36. Epigenetic Inheritance Emma Whitelaw, Henry Stewart Talks

37. Methylation of Agouti Genes in Mice Emma Whitelaw, Henry Stewart Talks

38. Reprogramming of Avy Allele in Development Emma Whitelaw, Henry Stewart Talks

39. Environment can Influence Epigenetic Changes Emma Whitelaw, Henry Stewart Talks

40. Bioactive Food Components in Epigenetic Processes Nutrients Polymorphisms SAH SAM CpG H3 Lys 4 Me-CpG Me-H3 Lys 4 Methyltransferases Demethylation Nutrients? Tumor

41. LTR Hypomethylated LTR Hypermethylated Maternal Supplements with zinc methionine choline folate B12 Yellow Mouse Agouti Mouse • Lower risk of cancer, diabetes, obesity • Prolonged life • High risk cancer, diabetes, obesity • Reduced lifespan Cooney et al. (2002) J Nutr. 132:2393S

42. Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase Activity Fang et al. Cancer Res. 63(22): 2003

43. Dietary Factors Influencing Histone Modifications

44. Histone Modifications • Covalent modification of histones: • Acetylation of lysines • Methylation of lysines and arginines • Phosphorylations of serines and threonines • ADP-ribosylation of glutamic acids • Ubiquitination of lysine residues • Sumolyation of lysine residues • Biotinylation of lysines

45. Epigenetic Mechanisms

46. Chromatin-Level Regulation of Gene Expression Inactive Chromatin SFN, DADS Garfinkel and Ruden Nutrition:20:56-62, 2004

47. Effects of Fatty Acids on Mammalian Cells in Culture Davie JR. J. Nutr. 133: 2485S-2493S, 2003

48. 1,25-Dihydroxyvitamin D(3) Stimulates Cyclic Vitamin D Receptor/Retinoid X Receptor DNA-Binding, Co-activator Recruitment, and HistoneAcetylation in Intact Osteoblasts. Kim S, Shevde NK, Pike JW.J Bone Miner Res. 2005 Feb;20(2):305-17. Epub 2004 Nov 16. • 1,25(OH)(2)D(3) induces rapid association of the VDR and RXR with both the Cyp24 and the Opn gene promoters in both MC3T3-E1 osteoblasts and MOBs • 1,25(OH)(2)D(3) treatment also induces rapid recruitment of co-regulators such as SRC-1, -2, and -3, CBP, and p300 to both promoters • Recruitment leads to acetylation of histone 4 on Cyp24 but not the Opn.

49. HistoneAcetylation

50. Histone Modification: