Epigenetic Mechanisms By Peyman GhoraishizadehDepartment 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 modificationsDefining code in every eukaryotic cellsGenetic 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&HeterochromatinHeterochromatin controls chromosomalStability and prevention ofMutations and translocationsHeterochromatin cause genomicImprinting 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 residuesDestabilise interactions between histone tailsand 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) residuesMethylation can result in activation or repressionOf expressiontrimethylation 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 CpGsites has been associated with the over-expression of oncogenes within cancer cells.
References• 1.http://en.wikipedia.org/wiki/Epigenetics• 2.Bird A.Nature ,447 ,396-98• 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
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