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 helix Nature 421,

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 off 0 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: Hyperacetylated histones Low DNA methylation H3-K4 methylation H4-K14 acetylation Hypoacetylated histones High DNA methylation H3-K9 methylation H4-K20 acetylation

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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