EPIGENETICSDr 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 • SumoylationAcetylation 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?