The diverse functions of histone lysine methylation

Abstract

DNA is packaged with histone proteins to form chromatin. The histone proteins are subject to numerous covalent modifications that regulate biological processes that are associated with chromatin, such as gene expression. A number of lysine residues within histones H3 and H4 are subject to methylation by site-specific enzymes. With regard to gene expression, some methylated lysines are involved in activation, whereas others are involved in repression. Current evidence suggests that methylated lysines within histones direct the recruitment of different methyl-binding proteins, which mediate the biological effects of lysine methylation. The methylation of H3 lysine 9 (H4-K9) and H4-K20 is involved in the formation of heterochromatin, a specific type of chromatin that is necessary for the proper functioning of centromeres and certain recombination events. Although the function of H4-K20 methylation is unclear, the methylation of H3-K9 functions in the recruitment of Swi6 or its mammalian homologue HP1. Recently, it has been demonstrated that the RNA interference pathway is critical for the recruitment of methyltransferases to sites of heterochromatin formation. The methylation of H3-K9 and H3-K27 has been linked to gene silencing. H3-K9 methylation seems to direct the recruitment of HP1 to several cell-cycle-regulated genes to silence gene expression. H3-K27 methylation is mediated by enzyme complexes composed of members of the Polycomb Group (PcG). PcG proteins have a role in a number of silencing phenomena including homeotic gene silencing, X-inactivation and imprinting. K4, K36 and K79 within histone H3 are associated with the positive regulation of gene expression. The enzymes that mediate H3-K4 and H3-K36 methylation are associated with the transcriptional machinery, and these modifications are established during transcriptional elongation. H3-K4 methylation has been shown to function as a binding site for severalenzymes that are involved in gene expression, including chromatin remodelling enzymes, histone acetyltransferases and lysine methyltransferases. Recently, studies have provided convincing evidence that histone lysine methylation can be reversed, thereby providing an additional level of control. LSD1 demethylates H3-K4 and H3-K9 through an amine oxidase reaction and seems to function as both a positive and negative regulator of gene expression.