Epigenetic phenomena are changes in gene expression and

Epigenetic phenomena are changes in gene expression and chromatin configuration which are independent from DNA sequence, hence genetics.

Epigenome provides instructions and regulates the functional aspects of all the genes

Monozygous twins share a common genotype and are genetically identical There is significant phenotypic discordance: ØMental disorders ØCancer

Epigenetics -DNA methylation -Histone PTMs (NC RNAs)

H 2 B: 19 Lysines 5 11 12 15 16 20 23 24 27 30 34 43 46 PEPAKSAPAPKKGSKKAVTKAQKKDGKERKRSRKESYSIYVYKVLKQV a 1 57 85 HPDTGISSKAMGIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRL a 2 L 1 108 116 120 L 2 125 LLPGELAKHAVSEGTKAVTKYTSSK LC a. C a 3

H 2 B: 14 modified Lysines (mass-spec) Me Ac Ac. Ac 5 11 12 Ac. Ac 15 16 Ac 20 Me Ac. Ac 23 24 Me 27 30 34 43 46 PEPAKSAPAPKKGSKKAVTKAQKKDGKERKRSRKESYSIYVYKVLKQV a 1 Me Ac 57 85 HPDTGISSKAMGIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRL a 2 L 1 Ac 108 Ac 116 Ub Ac 120 L 2 125 LLPGELAKHAVSEGTKAVTKYTSSK LC a. C a 3

H 2 B: abs against modified Lysines Me Ac. Ac Me Ac 5 11 12 Ac. Ac 15 16 Ac 20 Me Ac. Ac 23 24 Me 27 30 34 43 Me Ac 46 PEPAKSAPAPKKGSKKAVTKAQKKDGKERKRSRKESYSIYVYKVLKQV a 1 Me Ac 57 85 HPDTGISSKAMGIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRL a 2 L 1 Ac 108 Ac 116 Ub Ac 120 L 2 125 LLPGELAKHAVSEGTKAVTKYTSSK LC a. C a 3

Transcriptionally active chromatin regions tend to be hyperacetylated and hypomethylated. If a region of DNA or a gene is destined for silencing, chromatin remodeling enzymes such as histone deacetylases and ATP-dependent chromatin remodelers likely begin the gene silencing process. One or more of these activities may recruit DNA methyltransferase resulting in DNA methylation, followed finally by recruitment of the methyl-Cp. G binding proteins. The region of DNA will then be heritably maintained in an inactive state.

Age Dependent Epigenetic differences in Monozygotic (MZ) twins

Influence of Age on the Epigenome in MZ Twins ØIn the early years of life the younger MZ twins are epigenetically indistinguishable ØOlder MZ twins exhibit remarkable differences in their epigenome as evidenced by changes in the: voverall content and genomic distribution of 5 methylcytosine DNA and vhistone acetylation, affecting their gene-expression portrait.

The epigenome of our cells changes following changes in the environment and diet. The genome is the same in every cell (bar few exceptions).

Environment & Epigenome Mounting evidence suggests that fetuses are surprisingly susceptible to outside influences such as environmental pollutants, pesticides, and other toxins.

Agouti “Twin” Sisters

Coat color serves as a sensor for the degree of methylation present

Wolff et al. showed that providing excess folic acid, vitamin B-12, choline, and betaine to female mice before and during pregnancy shifts the coat color of their Avy/a offspring toward the brown (pseudoagouti) phenotype. Waterland Jirtle later demonstrated that this nutritionally induced change in phenotype occurs by increasing methylation at the Avy locus. Hence, the establishment of Cp. G methylation at Avy is sensitive to a dietary supplementation regimen designed to increase the efficiency of HCY remethylation.

. Waterland R A J. Nutr. 2006; 136: 1706 S-1710 S © 2006 by American Society for Nutrition

. Waterland R A J. Nutr. 2006; 136: 1706 S-1710 S © 2006 by American Society for Nutrition

The Dutch famine of 1944/45

Global perturbations of histones PTMs in human cancers. H 3 K 20 me 3 Lymphoma mouse SCC Fraga et al. Nat Genet. 2005. H 3 K 16 ac (MOF) Lymphoma Breast, Medulloblastoma Fraga et al. Nat Genet. 2005. H 3 K 4 me 2 (MLL) Prostate Seligson et al. Nature. 2005. H 3 K 18 ac Prostate Seligson et al. Nature. 2005. H 3 K 9 me 2 Prostate, Kidney Seligson et al. Am J Pathol. 2009. Ellinger et al. Prostate 2010. H 3 K 18 ac Lung, Kidney Seligson et al. Am J Pathol. 2009. Ellinger et al. Prostate 2010. H 3 K 27 me 3 (Pg) Prostate Yu et al. Caner Res. 2007. Pfister ey al. Int J Cancer 2008.

SUZ 12 Colon Prostate Colon Breast Skin Liver Lymphoma Liver Myeloma Endometrial Bladder Lung Gastric EZH 2

ASH 2 L: important for trymetilation of H 3 K 4 MEN 1 Molecular regulation of H 3 K 4 trimethylation by ASH 2 L, a shared subunit of MLL complexes Melissa M Steward 1, Jung-Shin Lee 1, Aisling O’Donovan 2, Matt Wyatt 1, Bradley E Bernstein 2 & Ali Shilatifard 1, 3 SEPTEMBER 2006 NATURE STRUCTURAL & MOLECULAR BIOLOGY

With minor exceptions, all differentiation processes are triggered and maintained through epigenetic mechanisms.

Epigenetic inheritance is an essential mechanism that allows the stable propagation of gene activity states from one generation of cells to the next.

DNA Is Not Destiny The science of epigenetics rewrites the rules of disease, heredity and identity.