Download Epigenetics - Hospital Melaka Department of Medicine Haematology

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?