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Does your DNA define you?
Overview of epigenetics and its role in disease
Epigenetics
epi (Greek): on, above, in addition to
The study of heritable changes in gene expression without a
change in DNA sequence
Image taken from Felsenfeld and Groudine (2003) Controlling
the double helixNature 421, 448-453
Image taken from Luger et al., (1997) Crystal structure of the nucleosome core particle at 2.8Å resolution. Nature 389, 251.
DNA
Histone tails
Turn genes on
or off0
F: turn genes on
Turn genes on
Turn genes off
R: Turn genes off
Image taken from Jenuwein and Allis (2001) Translating the histone code Science 293; 5532:1074-1080
• Hyperacetylated histones
• Low DNA methylation
• H3-K4 methylation• H4-K14 acetylation
• Hypoacetylated histones
• High DNA methylation
• H3-K9 methylation• H4-K20 acetylation
Environment
Genome Epigenome Intermediate phenotype Disease
ChemicalRadiation
AlcoholSmokingPollutionDiet
Epigenetics and disease
• Epigenetics provides the missing link on how the environment can change the cell without causing mutation to cause disease
• Studies have shown that modifications can be passed down from generation to generation and can be associated with causing or predisposing disease in offspring
Epigenetic therapy?
• The epigenome is dynamic with the modifications reversible. Because of this, it is possible to modify the gene expression of cells using drugs so abnormal patterns become normal
E.g. 5-azacytidine: DNA methylation inhibitor (cytosine analogue) that reactivates genes that have been silenced.
E.g. SAHA: HDAC inhibitor that blocks acetyl group removal from histones to activate gene expression.
Turn genes off
Turn genes on
SAHA
Turn genes on
5-azacytidine
R: Turn genes off