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.
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We are grateful to D. Reinberg for useful discussions and for generously providing several antibodies used in this study. We thank D. Ayer for providing Sin3A antibodies, K. Riabowol for providing ING1/2 antibodies, W. Lane for assistance with mass spectrometric analysis of Sin3A complexes, and S.E. Millman for technical assistance. We thank A. Heguy and the NYU Genome Techology Center for assistance with Illumina sequencing. This work was supported by NIH grant 2R01CA077245 and 2R01GM067132 to B.D.D.