Role of Histone H3 Lysine 4 Methylation in Chromatin Biology.

Specific expression of genes is fundamental for defining the identity and the functional state of cells. Sequence-specific transcription factors interpret the information contained in DNA sequence motifs and recruit cofactors to modify chromatin and control RNA polymerases. This multi-step process typically involves several transcription factors and cofactors with different enzymatic activities. Post-translational modifications (PTMs) of histones are one key mechanism to control chromatin structure and polymerase activity and thus gene transcription. The methylation of histone H3 at lysine 4 (H3K4) is a modification of accessible chromatin, including enhancers and promoters, and also sites of recombination and some forms of DNA damage. H3K4 methylation is catalyzed by six lysine methyltransferase complexes, referred to as KMT2 or COMPASS-like complexes. These are important in processes related to transcription and contribute to recombination in T and B cells. PRDM9 and ASH1L are H3K4 methyltransferases involved in meiotic recombination and DNA repair, respectively. In transcription, H3K4 mono- and tri-methylation are located at enhancers and promoters, respectively. These modifications, either alone or in combination with other histone PTMs, provide binding sites for transcriptional cofactors. Through these sites, H3K4 methylation affects chromatin accessibility and histone PTMs, typically resulting in a favorable environment for transcription. H3K4 tri-methylation also recruits and regulates RNA polymerase II (RNAPII) complexes, which interact with KMT2 complexes, generating positive feedforward loops to promote transcription. Thus, H3K4 methylation has broad activities that are key to different chromatin-associated processes.