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histone modifications

Sunday 19 March 2006

The human genome contains 23 000 genes that must be expressed in specific cells at precise times. Cells manage gene expression by wrapping DNA around clusters (octamers) of globular histone proteins to form nucleosomes. These nucleosomes of DNA and histones are organized into chromatin.

Changes to the structure of chromatin influence gene expression: genes are inactivated (switched off) when the chromatin is condensed (silent), and they are expressed (switched on) when chromatin is open (active).

These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modifications.

Enzymes involved in this process include DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone acetylases, histone methyltransferases and the methyl-binding domain protein MECP2.

Alterations in these normal epigenetic patterns can deregulate patterns of gene expression, which results in profound and diverse clinical outcomes.

Histone modifications

Histone proteins can be mono-, di-, or trimethylated at the amino group of lysine residues and either mono- or dimethylated at arginine residues. In combination with other covalent modifications such as acetylation, phosphorylation, and ubiquitination, methylations of histone proteins are thought to represent an epigenetic code by the creation of binding interfaces for proteins involved in chromatin regulation.

Several SET (SuVar39, Enhancer of Zeste, and Trithorax) domain proteins have been demonstrated to be methyltransferases capable of covalently altering the lysine residues of histone proteins. Many SET domain proteins have been tightly linked to cancer development and in the following section.