Spacial Topics in Human Genetics Subject: Epigenetics by:Mohammad Hossein Bakhshi Aliabad Peyman Ghoraishizadeh
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.
Cancer epigenetics is the study of epigenetic modifications to the genomeof cancer cells that do not involve a change in the nucleotide sequence. Epigeneticalterations are as important as genetic mutations in a cell’s transformation tocancer.Mechanisms of epigenetic silencing of tumor suppressor genes and activationof oncogenes include: alteration in CpG island methylationpatterns, histone modifications. Epigenetic modifications in Neurodevelopmental disordersGenetic mutations in epigenetic genes cause dysfunctions that lead to certainneurodevelopmental disorders, The majority of the evidence centers on DNAmethylation and histone modification. Epigenetic modifications in autoimmune diseasesAutoimmune diseases are characterized by the breakdown of immunetolerance to specific self-antigens.
• So if you do something during your life that gives you a specific Epigenome will it be passed down? Yes ? No ?
Sometimes yes and some times no …An experiment was done with genetically identical mice. Most were fat but somewere skinny. Both these mice have a one gene called agouti but in the yellowmouse it stays on all of the time, and this causes obesity.So why is the thin mouse is thin, if they are genetically identical? •Well, in the brown (thin) mouse there is a tiny chemical “tag” that has attached itself to the agouti gene shutting it down. •In order to get thin brown mice instead of fat yellow mice, you can feed the pregnant mothers a diet rich in methyl groups to form tags and ultimately turn the gene off. This dramatically shifted the coat color from yellow to brown and produced many more brown mice. •This is important because the coat color is a tracer, or an indicator that the gene is in fact turned off. This shift of the phenotype is called an epigenetic fix, and it was also inherited by the next generation of mice, regardless of what their mothers ate.
Enviromental and Dietary factors have an important role in abnormalepygnetics pathway.For example:Smoking : causes Demethylation of metastatic genes in lung cancer cells.Cadmium: is a heavy metal that causes deformity in DNA methylation.Pesticide: changes the DNA methylation.folate and methionine : they supply methyl group for DNA methylation.
DRUGS1. Inhibitors of DNA methyltransferases, Azacitidine for breast cancer2. Inhibitors of histone deacetylases, Trichostatin for breast cancer3. Histone acetyltransferases.4. Histone methyltransferases.5. Histone demethylases.
The epigenome shows far greater plasticity than the genome and contributessignificantly to development and differentiation by responding to environmentalstimuli. Errors in epigenetic programming caused by genetic defects and/orenvironmental factors have been directly implicated with human disease.
The Epigenome never actually does the work. Thegenome does the work that the Epigenome tells itto do.
Conclusion• the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases.• For example: Unmethylated CpG sites can be detected by Toll-Like Receptor 9 (TLR 9) on plasmacytoid dendritic cells and B cells in humans and it can be used to detect intracellular viral, fungal, and bacterial pathogen DNA.
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