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Epigenetics
1. Spacial Topics in Human Genetics
Subject: Epigenetics
by:
Mohammad Hossein Bakhshi Aliabad
Peyman Ghoraishizadeh
2. 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)
3. 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 same
Epigenetic code is tissue and cell specific (3)
6. Nucleosome
• nucleosome contains
147 bp of genomic DNA
wrapped around an
octamer of histone
Proteins approximately
1.75 times
7. 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
9. 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)
11. 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)
13. 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.
15. Cancer epigenetics is the study of epigenetic modifications to the genome
of cancer cells that do not involve a change in the nucleotide sequence. Epigenetic
alterations are as important as genetic mutations in a cell’s transformation to
cancer.
Mechanisms of epigenetic silencing of tumor suppressor genes and activation
of oncogenes include: alteration in CpG island methylation
patterns, histone modifications.
Epigenetic modifications in Neurodevelopmental disorders
Genetic mutations in epigenetic genes cause dysfunctions that lead to certain
neurodevelopmental disorders, The majority of the evidence centers on DNA
methylation and histone modification.
Epigenetic modifications in autoimmune diseases
Autoimmune diseases are characterized by the breakdown of immune
tolerance to specific self-antigens.
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20. • So if you do something during your life that gives
you a specific Epigenome will it be passed down?
Yes ? No ?
21. Sometimes yes and some times no …
An experiment was done with genetically identical mice. Most were fat but some
were skinny. Both these mice have a one gene called agouti but in the yellow
mouse 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.
22. Enviromental and Dietary factors have an important role in abnormal
epygnetics 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.
23. DRUGS
1. Inhibitors of DNA methyltransferases, Azacitidine for breast cancer
2. Inhibitors of histone deacetylases, Trichostatin for breast cancer
3. Histone acetyltransferases.
4. Histone methyltransferases.
5. Histone demethylases.
24. The epigenome shows far greater plasticity than the genome and contributes
significantly to development and differentiation by responding to environmental
stimuli. Errors in epigenetic programming caused by genetic defects and/or
environmental factors have been directly implicated with human disease.
25. The Epigenome never actually does the work. The
genome does the work that the Epigenome tells it
to do.
26. 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.
27. 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