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Epigenetics

Epigenetics. Dr Guan Yong Khee. BUILDING BLOCKS OF ALL ORGANISM…. Cells  Tissue  Organ  Organism. Eukaryotic Animal Cell. CHROMOSOMES…. DNA - the molecule of Life. Watson and Crick deduced the structure of DNA in 1953 at the MRC unit in Cambridge.

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Epigenetics

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  1. Epigenetics Dr Guan Yong Khee

  2. BUILDING BLOCKS OF ALL ORGANISM… • Cells  Tissue  Organ  Organism

  3. Eukaryotic Animal Cell

  4. CHROMOSOMES…

  5. DNA - the molecule of Life

  6. Watson and Crick deduced the structure of DNA in 1953 at the MRC unit in Cambridge

  7. Watson and Crick, with Wilkins, were awarded the Nobel Prize for Medicine in 1962

  8. Human Genome Project • The $3-billion project was formally founded in 1990 by the US Department of Energy and the National Institutes of Health • A 'rough draft' of the genome was finished in 2000, announced jointly by U.S. President Bill Clinton and the British Prime Minister Tony Blair on June 26, 2000 • Essentially complete genome in April 2003

  9. What is Epigenetics?

  10. Epigenetics Study of changes in gene expression or cellular phenotype • caused by mechanisms other than changes in the underlying DNA sequence Epi – Greek for “over” or “on top of”

  11. Why does’t every cell that has the same DNA looks the same?

  12. Different genes are turned on and different genes are turned off in the development of different tissues/cells

  13. Human Genome Project = Road Map of DNA

  14. EPIGENETICS = GPS

  15. How can cells do that? • By a few postulated mechanisms • Mainly • DNA methylation • Histone modification

  16. DNA methylation

  17. DNA methylation • Highly methylated areas tend to be less transcriptionally active

  18. Mechanism • Post translational modification of Histone proteins

  19. Post translational modification of Histone proteins Modifications include: • Acetylation • Methylation • Ubiquitylation • Phosphorylation • Sumoylation Acetylation is the most highly studied of these modifications

  20. Epigenetics in Cancer and Haematology

  21. Epigenetics in Cancer and Haematology • Aberrant DNA methylation is associated with unscheduled gene silencing • Hypermethylation  repress transcription via promoter region of tumour suppressor genes

  22. Drugs currently in use

  23. Hypomethylating agents • Decitabine • 5-azacytidine • Cytarabine Currently used in treatment of Myelodysplastic Syndromes and AML

  24. Histone deacetylase inhibitors • Vorinostat • Romidepsin • Panobinostat • Valproic Acid Currently used in treatment of certain lymphomas

  25. Questions remains • How to control which switches to turn on and which ones to turn off?

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