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 Myoblasts can only form muscle cellso Keratinocytes only form skin cells o Hematopoetic cells only become blood cellso 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 Myoblasts can only form muscle cellso Keratinocytes only form skin cells o Hematopoetic cells only become blood cellso But all have identical DNA sequences




• 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 Myoblasts can only form muscle cellso Keratinocytes only form skin cells o Hematopoetic cells only become blood cellso But all have identical DNA sequences.




• 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


Methylation of Cytosine in DNA


5-Methyl Cytosine in DNA


Cytosine Methylation MaintainsInactive-Condensed Chromatin State

Transcription factorsRNA polymerase

Transcription Acetylation

DNA methyltransferase 5-methyl-C

Methyl-CpGBinding proteinsand associated

co-repressors

Histone deacetylase

Transcription blocked

XDeacetylation

Chromatin compactionTranscriptional silencing

Alex Meissner, Henry Stewart Talks

5-Methyl Cytosine is Found in Heterochromatic Regions

John Greally, Henry Stewart Talks

Structure & Epigenetics ofEuchromatin versus Heterochromatin


Me

Maintenance ofCytosine Methylation

Alex Meissner, Henry Stewart TalksAlex Meissner, Henry Stewart Talks

Passive Demethylation of5-Methyl-Cytosine

Alex Meissner, Henry Stewart TalksAlex Meissner, Henry Stewart Talks

Establishment and Maintenance ofCytosine Methylation


Some DNA Methyl Transferases are Essential


Methylated DNA from Zygote to Adult


DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult

Stem Cells


Critical CpG Sequences inCpG Islands Near Promoters


Organization of the Epigenome


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


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 H4

Barbara Migeon, Henry Stewart Talks

Agouti Genes in Mice

Emma Whitelaw, Henry Stewart Talks

Epigenetic Inheritance


Methylation of Agouti Genes in Mice


Reprogramming of Avy Allele in Development


Environment can Influence Epigenetic Changes


Tumor

Bioactive Food Components in Epigenetic Processes

Methyltransferases

Demethylation

Nutrients?

CpGH3 Lys 4

Me-CpG Me-H3 Lys 4

SAM

Nutrients

SAH

Polymorphisms

Yellow Mouse Agouti Mouse

Cooney et al. (2002) J Nutr. 132:2393S

Maternal Supplements

withzinc

methioninecholinefolateB12

• High risk cancer, diabetes, obesity

• Reduced lifespan

• Lower risk of cancer, diabetes, obesity

• Prolonged life

LTR Hypomethylated LTR Hypermethylated

Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA

Methyltransferase Activity

Fang et al. Cancer Res. 63(22): 2003

Dietary Factors Influencing 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

Histone Modifications

Epigenetic Mechanisms

Chromatin-Level Regulation of Gene Expression

Garfinkel and Ruden Nutrition:20:56-62, 2004

Inactive Chromatin

SFN, DADS

No. of carbons in fatty acid

Effect on fibroblast growth % control

Induction of alkaline phosphatase (HeLa) % control

Inhibition of estradiol-induced synthesis of transferring mRNA

Inhibition of histone deacetylase (calf thymus)

C2, acetate 82 170 18 10

C3, propionate

45 160 77 60

C4, butyrate 0 630 95 80

C5, valeroic 71 420 — 65

C6, caproate — 120 — 30

Effects of Fatty Acids on Mammalian Cells in Culture

Davie JR. J. Nutr. 133: 2485S-2493S, 2003

1,25-Dihydroxyvitamin D(3) Stimulates Cyclic Vitamin D Receptor/Retinoid X Receptor DNA-

Binding, Co-activator Recruitment, and Histone Acetylation 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.

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 H3K4methyl).

• 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.

Identical Twins with Different Hair Color

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