Epigenetic Mechanisms

By Peyman Ghoraishizadeh

Department of Obstetric& Gynecology

Universiti Putra Malaysia

Definition of Epigenetics• Changes in gene expression or phenotype that don’t involve changes

to the DNA sequence(1)

• Its defined as heritable changes in gene activity and expression that

occur without alteration in DNA sequence (2)

Mechanism of Epigenetics• Mechanisms Chromatin Remodelling & Histone Modification

DNA Methylation

Non-coding RNA mediated pathway

Prion

Epigenetic code:

Consist of Both DNA methylation and histone modifications Defining code in every eukaryotic cells

Genetic code in each cell is the sameEpigenetic code is tissue and cell specific (3)

Chromatin structure • Chromatin= DNA+ Protein • Basic unit of chromatin is nucleosome• Chromatin structure is dynamic

Euchromatin&Heterochromatin

Heterochromatin controls chromosomal

Stability and prevention of

Mutations and translocations

Heterochromatin cause genomic

Imprinting and

X chromosomal inactivation

Nucleosome • nucleosome contains

147 bp of genomic DNA wrapped around an octamer of histone Proteins approximately 1.75 times

Chromatin remodeling • Chromatin remodeling is accomplished through

two main mechanisms:• Post trans translational modification of the amino acids

that make up histone protein• Addition of methyl group to DNA

Histone Modifications • Post-translational modifications:• – Acetylation – Lys• – Methylation – Lys and Arg• – Phosphorylation – Ser and Thr • – Ubiquitination – Lys

Histone Acetylation&Deacetylation • Histone acetylation• – Histone acetyl transferases (HATs)• Adds acetyl groups to histone tails• Reduces positive charge and weakens interaction of histones with DNA• Facilitates transcription by making DNA more accessible to RNA polymerase II• Histone deacetylation• – Histone deacetylases (HDACs)• Removes acetyl groups from histone tails• Increases interaction of DNA and histones• Represses transcription (usually)

Histone Acetylation&Deacetylation

• Acetylation has two functions:

reduce the positive charge on the lysine residues

Destabilise interactions between histone tails

and structural proteins

Histone Methylation

• Histone methylation • Histone methyl transferases (HMTs)

– Histone lysine methyl transferases(HKMTs)

.Methylate lys (k) residues

. Protein argenin methyl transferase (PRMTs)

.Methylate arge(R) residues

Methylation can result in activation or repression

Of expression

trimethylation of histone H3 at lysine 4 (H3K4) is an active mark for transcription  dimethylation of histone H3 at lysine 9 (H3K9), a signal for transcriptional silencing (4)

• Small Ubiquitin-like Modifier (or SUMO) proteins

• Ubiquitin

• ADP-ribosylation

DNA Methylation • Involves the addition of a methyl group to DNA• Usually to the number 5 carbon of the cytosine • pyrimidine ring• Effect: reducing gene expression• Catalyzed by DNA methyltransferases (DNMTs)• Predominantly found found in CpG sites of mammalian genome

Silencing:

• Methylation of CpG sites within the promoters of genes can lead to their

silencing, a feature found in a number of human cancers (eg. silencing of tumor

• suppressor genes)

Activation:

• In contrast, the hypomethylation of CpG

sites has been associated with the over-expression of oncogenes within cancer cells.

Epigenetic and gene regulation

References • 1.http://en.wikipedia.org/wiki/Epigenetics• 2.Bird A.Nature ,447 ,396-98[2007]• 3. Turner B (2007). "Defining an epigenetic code". Nat Cell Biol 9 (1): 2–6.

•  4.Gupta, Swati; Se Y. Kim, Sonja Artis, David L. Molfese, Armin Schumacher, J. David Sweatt, Richard E. Paylor, and Farah D. Lubin (10 March 2010). "Histone Methylation Regulates

Memory Formation". The Journal of Neuroscience 30 (10): 3589–3599