A Role for H3K4 Monomethylation in Gene Repression and Partitioning of Chromatin Readers

Monomethylation of lysine 4 on histone H3 (H3K4me1) is a well-established feature of enhancers and promoters, although its function is unknown. Here, we uncover roles for H3K4me1 in diverse cell types. Remarkably, we find that MLL3/4 provokes monomethylation of promoter regions and the conditional repression of muscle and inflammatory response genes in myoblasts. During myogenesis, muscle genes are activated, lose MLL3 occupancy, and become H3K4-trimethylated through an alternative COMPASS complex. Monomethylation-mediated repression was not restricted to skeletal muscle. Together with H3K27me3 and H4K20me1, H3K4me1 was associated with transcriptional silencing in embryonic fibroblasts, macrophages, and human embryonic stem cells (ESCs). On promoters of active genes, we find that H3K4me1 spatially demarcates the recruitment of factors that interact with H3K4me3, including ING1, which, in turn, recruits Sin3A. Our findings point to a unique role for H3K4 monomethylation in establishing boundaries that restrict the recruitment of chromatin-modifying enzymes to defined regions within promoters. [Display omitted] •H3K4me1 marks inducible genes in ESC, macrophages, and muscle•MLL3/4 recruitment to promoters mediates H3K4me1, which leads to gene silencing•H3K4me3 and sequence-specific factors “multivalently” recruit Sin3 to chromatin•H3K4me1 at promoters establishes a “boundary” for Sin3 recruitment Monomethylation of histone H3 at lysine 4 (H3K4Me1) is a feature of enhancers and promoters. Cheng et al. find that MLL3/4-dependent H3K4Me1 influences both repressed and active promoters. Repressed promoters are covered by H3K4me1, which promotes gene repression along with H3K27me3 and H4K20me1. On active promoters it restricts recruitment of H3K4Me3 binding proteins.