title: A role for H3K4 monomethylation in gene repression and partitioning of chromatin readers.
abstract: 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.
authors.affiliation: Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jemmie
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Blum
authors.affiliation: Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bowman
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Hu
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
authors.affiliation: GTC, Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: brian.dynlacht@nyumc.org.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dynlacht
mesh_terms: D000818:Animals; D002843:Chromatin; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; C452979:KMT2C protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human; D056264:Sin3 Histone Deacetylase and Corepressor Complex