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Pathway Description:

The nucleosome, made up of four histone proteins (H2A, H2B, H3, and H4), is the primary building block of chromatin. Originally thought to function as a static scaffold for DNA packaging, histones have more recently been shown to be dynamic proteins, undergoing multiple types of post-translational modifications. One such modification, methylation of lysine residues, is a major determinant for formation of active and inactive regions of the genome. A set of histone lysine methyltransferases have been identified, all but one of which contain a conserved catalytic SET domain originally identified in the Drosophila Su[var]3-9, Enhancer of zeste, and Trithorax proteins. Lysine methylation has been implicated in both transcriptional activation (H3 Lys4, 36, 79) and silencing (H3 Lys9, 27, H4 Lys20).

Unlike acetylation, methylation does not alter the charge of lysine residues and is unlikely to directly modulate nucleosomal interactions required for chromatin folding. Lysine methylation coordinates the recruitment of chromatin modifying enzymes. Chromodomains (HP1, PRC1), PHD fingers (BPTF, ING2), Tudor domains (53BP1), and WD-40 domains (WDR5) are among a growing list of methyl-lysine binding modules found in histone acetyltransferases, deacetylases, methylases, and ATP-dependent chromatin remodeling enzymes. Lysine methylation provides a binding surface for these enzymes, which then regulate chromatin condensation and nucleosome mobility in order to maintain local regions of active or inactive chromatin. In addition, lysine methylation can block binding of proteins that interact with unmethylated histones or directly inhibit catalysis of other regulatory modifications on neighboring residues. The presence of methyl-lysine binding modules in the DNA repair protein 53BP1 suggests roles for lysine methylation in other cellular processes.

Histone methylation is crucial for proper programming of the genome during development, and misregulation of the methylation machinery can lead to diseased states such as cancer. Until recently, methylation was believed to be an irreversible, stable epigenetic mark that is propagated through multiple cell divisions, maintaining a gene in an active or inactive state. While there is no argument that methylation is a stable mark, recent identification of histone demethylases such as LSD1/AOF2, JMJD1, JMJD2, and JHDM1 has shown that methylation is reversible and provides a rationale for how genomes might be reprogrammed during differentiation of individual cell lineages.

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created May 2006

revised September 2012