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Identical Twins with Different Hair Color. 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
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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?
Mosaicism:An Individual with Two Different Eye Colors “Diego”
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?
Coat Colors of Genetically Identical Agouti Mice Liter Mates
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!
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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)
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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
Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase Activity Fang et al. Cancer Res. 63(22): 2003
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
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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.