L’ ‘epigenetica’ si riferisce a tutti i cambiamenti dell’espressione genica e dell’organizzazione della cromatina che sono indipendenti dalla sequenza del DNA.

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: Ø Mental disorders Ø Cancer

Epigenetics -DNA methylation -Histone PTMs (NC RNAs)

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-CpG binding proteins. The region of DNA will then be heritably maintained in an inactive state.

Age Dependent Epigenetic differences in Monozygotic (MZ) twins

Ø In the early years of life the younger MZ twins are epigenetically indistinguishable

Ø Older MZ twins exhibit remarkable differences in their epigenome as evidenced by changes in the: v overall content and genomic distribution of 5-methylcytosine DNA and

v histone acetylation, affecting their gene-expression portrait.

Influence of Age on the Epigenome in MZ Twins

L’epigenetica è al centro della medicina moderna in quanto l’epigenoma delle nostre cellule cambia nel tempo in seguito a cambiamenti ambientali e dietetici, al contraio del genoma, che è lo stesso in ogni cellula.

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

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Waterland R A J. Nutr. 2006;136:1706S-1710S

©2006 by American Society for Nutrition

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 and Jirtle later demonstrated that this nutritionally induced change in phenotype occurs by increasing methylation at the Avy locus. Hence, the establishment of CpG methylation at Avy is sensitive to a dietary supplementation regimen designed to increase the efficiency of HCY remethylation.

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Waterland R A J. Nutr. 2006;136:1706S-1710S

©2006 by American Society for Nutrition

Global perturbations of histones PTMs in human cancers.

H3K4me2 (MLL) Prostate Seligson et al. Nature. 2005.

H3K20me3 Lymphoma Fraga et al. Nat Genet. 2005. mouse SCC

H3K18ac Prostate Seligson et al. Nature. 2005.

H3K16ac (MOF) Lymphoma Fraga et al. Nat Genet. 2005. Breast, Medulloblastoma Pfister ey al. Int J Cancer 2008.

H3K9me2 Prostate, Kidney Seligson et al. Am J Pathol. 2009. Ellinger et al. Prostate 2010.

H3K18ac Lung, Kidney Seligson et al. Am J Pathol. 2009. Ellinger et al. Prostate 2010.

H3K27me3 (Pg) Prostate Yu et al. Caner Res. 2007.

Liver

Breast

Colon SUZ12

Gastric

Lung

Endometrial

Liver

Skin

Colon

Bladder

Myeloma

Lymphoma

Breast

Prostate EZH2

ASH2L: important for trymetilation of H3 K4

Molecular regulation of H3K4 trimethylation by ASH2L,

a shared subunit of MLL complexes Melissa M Steward1, Jung-Shin Lee1, Aisling O’Donovan2,Matt Wyatt1,

Bradley E Bernstein2 & Ali Shilatifard1,3 SEPTEMBER 2006 NATURE STRUCTURAL & MOLECULAR

BIOLOGY

MEN1

MEN1

MEN1

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.