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Transcript
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 Watson and Crick, with Wilkins, were awarded the Nobel Prize for Medicine in 1962 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 WHAT IS EPIGENETICS? 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” WHY DOES’T EVERY CELL THAT HAS THE SAME DNA LOOKS THE SAME? Different genes are turned on and different genes are turned off in the development of different tissues/cells Human Genome Project = Road Map of DNA EPIGENETICS = GPS HOW CAN CELLS DO THAT? By a few postulated mechanisms Mainly DNA methylation Histone modification DNA methylation DNA METHYLATION Highly methylated areas tend to be less transcriptionally active MECHANISM Post translational modification of Histone proteins POST TRANSLATIONAL MODIFICATION OF HISTONE PROTEINS Modifications include: • Acetylation • Methylation • Ubiquitylation • Phosphorylation • Sumoylation Acetylation is the most highly studied of these modifications EPIGENETICS IN CANCER AND HAEMATOLOGY EPIGENETICS IN CANCER AND HAEMATOLOGY Aberrant DNA methylation is associated with unscheduled gene silencing Hypermethylation repress transcription via promoter region of tumour suppressor genes DRUGS CURRENTLY IN USE HYPOMETHYLATING AGENTS Decitabine 5-azacytidine Cytarabine Currently used in treatment of Myelodysplastic Syndromes and AML HISTONE DEACETYLASE INHIBITORS Vorinostat Romidepsin Panobinostat Valproic Acid Currently used in treatment of certain lymphomas QUESTIONS REMAINS How to control which switches to turn on and which ones to turn off?
