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

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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.

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SAHA

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5-azacytidine

R: Turn genes off