Identical Twins with Different Hair Color What is
- Slides: 52
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? o o 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”
Mosaicism: An Individual Eye with Two Colors
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? o o • • 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? o o • • • 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!
DNA Methylation & the Epigenetic Code Paula Vertino, Henry Stewart Talks
DNA Methylation & Histone Modifications Form the Epigenetic Code Paula Vertino, Henry Stewart Talks
Methylation of Cytosine in DNA Paula Vertino, Henry Stewart Talks
5 -Methyl Cytosine in DNA Paula Vertino, Henry Stewart Talks
Cytosine Methylation Maintains Inactive-Condensed Chromatin State Transcription factors RNA polymerase Transcription Acetylation DNA methyltransferase Methyl-Cp. G Binding proteins and associated co-repressors 5 -methyl-C Histone deacetylase Transcription blocked X Deacetylation Chromatin compaction Transcriptional silencing Alex Meissner, Henry Stewart Talks
5 -Methyl Cytosine is Found in Heterochromatic Regions John Greally, Henry Stewart Talks
Structure & Epigenetics of Euchromatin versus Heterochromatin Me Paula Vertino, Henry Stewart Talks
Maintenance of Cytosine Methylation Alex Meissner, Henry Stewart Talks
Passive Demethylation of 5 -Methyl-Cytosine Alex Meissner, Henry Stewart Talks
Establishment and Maintenance of Cytosine Methylation Alex Meissner, Henry Stewart Talks
Some DNA Methyl Transferases are Essential Alex Meissner, Henry Stewart Talks
Some DNA Methyl Transferases are Essential Alex Meissner, Henry Stewart Talks
Methylated DNA from Zygote to Adult Alex Meissner, Henry Stewart Talks
DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks
DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks
Critical Cp. G Sequences in Cp. G Islands Near Promoters Alex Meissner, Henry Stewart Talks
Organization of the Epigenome Paula Vertino, Henry Stewart Talks
Epigenetic Imprinting Marisa Bartolomei, Henry Stewart Talks
Methylation Changes During Development Marisa Bartolomei, Henry Stewart Talks
Demethylation of the Paternal Genome Adrien Bird, Henry Stewart Talks
Methylation Changes During Development Paula Vertino, Henry Stewart Talks
Methylation Changes During Development Paula Vertino, Henry Stewart Talks
Methylation Changes During Development Paula Vertino, Henry Stewart Talks
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)
X Chromosome Inactivation: CG Island Methylation Adrien Bird, Henry Stewart Talks
Only one X is active Barbara Migeon, Henry Stewart Talks
Inactive X has unacetylated histone H 4 Barbara Migeon, Henry Stewart Talks
Agouti Genes in Mice Emma Whitelaw, Henry Stewart Talks
Epigenetic Inheritance Emma Whitelaw, Henry Stewart Talks
Methylation of Agouti Genes in Mice Emma Whitelaw, Henry Stewart Talks
Reprogramming of Avy Allele in Development Emma Whitelaw, Henry Stewart Talks
Environment can Influence Epigenetic Changes Emma Whitelaw, Henry Stewart Talks
Bioactive Food Components in Epigenetic Processes Nutrients Polymorphisms SAH SAM Cp. G H 3 Lys 4 Methyltransferases Demethylation Nutrients? Tumor Me-Cp. G Me-H 3 Lys 4
LTR Hypomethylated LTR Hypermethylated Maternal Supplements with zinc methionine choline folate B 12 Yellow Mouse • High risk cancer, diabetes, obesity • Reduced lifespan Cooney et al. (2002) J Nutr. 132: 2393 S Agouti Mouse • Lower risk of cancer, diabetes, obesity • Prolonged life
Tea Polyphenol Epigallocatechin-3 -Gallate Inhibits DNA Methyltransferase Activity Fang et al. Cancer Res. 63(22): 2003
Dietary Factors Influencing Histone Modifications
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
Epigenetic Mechanisms
Chromatin-Level Regulation of Gene Expression Inactive Chromatin SFN, DADS Garfinkel and Ruden Nutrition: 20: 56 -62, 2004
Effects of Fatty Acids on Mammalian Cells in Culture No. of carbons in fatty acid Effect on fibroblast growth % control Induction of alkaline phosphatase (He. La) % control Inhibition of estradiol Inhibition of -induced synthesis of histone transferring m. RNA deacetylase (calf thymus) C 2, acetate 82 170 18 10 C 3, propionate 45 160 77 60 C 4, butyrate 0 630 95 80 C 5, valeroic 71 420 — 65 C 6, caproate — 120 — 30 Davie JR. J. Nutr. 133: 2485 S-2493 S, 2003
1, 25 -Dihydroxyvitamin D(3) Stimulates Cyclic Vitamin D Receptor/Retinoid X Receptor DNABinding, Co-activator Recruitment, and Histone Acetylation in Intact Osteoblasts. Kim S, Shevde NK, Pike JW. J Bone Miner Res. 2005 Feb; 20(2): 30517. Epub 2004 Nov 16. • 1, 25(OH)(2)D(3) induces rapid association of the VDR and RXR with both the Cyp 24 and the Opn gene promoters in both MC 3 T 3 -E 1 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 p 300 to both promoters • Recruitment leads to acetylation of histone 4 on Cyp 24 but not the Opn.
Histone Acetylation
Histone Modification:
Hongerwinter 1944 • • German’s blocked food to the Dutch in the winter of 1944. Calorie consumption dropped from 2, 000 to 500 per day for 4. 5 million. Children born or raised in this time were small, short in stature and had many diseases including, edema, anemia, diabetes and depression. The Dutch Famine Birth Cohort study showed that women living during this time had children 20 -30 years later with the same problems despite being conceived and born during a normal dietary state.
Summary of Epigenetic Gene Regulation • • • Patterns of DNA methylation in adult cells parallels cell fate, chromatin structure and gene activation. Most DNA methylation is removed at fertilization and re-established during embryogenesis. Imprinted genes keep their parental pattern of methylation giving rise to parental patterns of expression. Patterns of histone modifications parallel DNA methylation. Methylated gene regions are genetically inactive, highly condensed and special histone modifications. Active gene regions have little DNA methylation and distinctive histone modifications (acetyl groups and H 3 K 4 methyl). X chromosome inactivation in females is correlated with extensive CG island methylation on one chromosome, condensation, inactivation and Barr body formation. Alterations in gene and CG island methylation patterns are seen in aging and in cancer. Most CG islands are not methylated except for X chromosome inactivation and tumor suppressors in cancer.
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