Transcript L` `epigenetica` si riferisce a tutti i cambiamenti dell`espressione

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:
Mental disorders
Cancer
Epigenetics
-DNA methylation
-Histone PTMs
(NC RNAs)
H2B: 19 Lysines
5
11 12
15 16
20
23 24
27
30
34
43
46
PEPAKSAPAPKKGSKKAVTKAQKKDGKERKRSRKESYSIYVYKVLKQVH
a1
57
85
PDTGISSKAMGIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRLL
a2
L1
108
116
120
L2
125
LPGELAKHAVSEGTKAVTKYTSSK
LC
aC
a3
H2B: 14 modified Lysines (mass-spec)
Me
Ac
AcAc
AcAc
Ac
Me
AcAc
5
11 12
15 16
20
23 24
Me
27
30
34
43
46
PEPAKSAPAPKKGSKKAVTKAQKKDGKERKRSRKESYSIYVYKVLKQVH
a1
Me
Ac
57
85
PDTGISSKAMGIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRLL
a2
L1
Ac
Ac
Ub
Ac
108
116
120
L2
125
LPGELAKHAVSEGTKAVTKYTSSK
LC
aC
a3
H2B: abs against modified Lysines
Me
Ac
Me
AcAc
AcAc
Ac
Me
AcAc
5
11 12
15 16
20
23 24
27
30
34
Me
Me
Ac
43
46
PEPAKSAPAPKKGSKKAVTKAQKKDGKERKRSRKESYSIYVYKVLKQVH
a1
Me
Ac
57
85
PDTGISSKAMGIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRLL
a2
L1
Ac
Ac
Ub
Ac
108
116
120
L2
125
LPGELAKHAVSEGTKAVTKYTSSK
LC
aC
a3
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
Influence of Age on the Epigenome
in MZ Twins
In the early years of life the younger MZ
twins are epigenetically indistinguishable
Older MZ twins exhibit remarkable
differences in their epigenome as
evidenced by changes in the:
overall content and genomic distribution of 5methylcytosine DNA and
histone acetylation, affecting their gene-expression
portrait.
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
.
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.
.
Waterland R A J. Nutr. 2006;136:1706S-1710S
©2006 by American Society for Nutrition
Global perturbations of histones PTMs in human cancers.
H3K20me3
Lymphoma
mouse SCC
Fraga et al. Nat Genet. 2005.
H3K16ac (MOF)
Lymphoma
Breast, Medulloblastoma
Fraga et al. Nat Genet. 2005.
H3K4me2 (MLL)
Prostate
Seligson et al. Nature. 2005.
H3K18ac
Prostate
Seligson et al. Nature. 2005.
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.
Pfister ey al. Int J Cancer 2008.
SUZ12
Colon
Prostate
Colon
Breast
Breast
Skin
Liver
Lymphoma
Liver
Myeloma
Endometrial
Bladder
Lung
Gastric
EZH2
ASH2L: important for trymetilation of H3 K4
MEN1
MEN1
MEN1
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
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.