title: H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation.
abstract: Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.01503.001.
authors.affiliation: Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.forename: Shiliyang
authors.initials: S
authors.lastname: Xu
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Cho
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.forename: Xuesong
authors.initials: X
authors.lastname: Feng
authors.forename: Anne
authors.initials: A
authors.lastname: Baldridge
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.forename: Lenan
authors.initials: L
authors.lastname: Zhuang
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology*; D050156:Adipogenesis; D000818:Animals; D001665:Binding Sites; D019070:Cell Lineage; D019295:Computational Biology; D004257:DNA Polymerase II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D023281:Genomics / Q000379:methods; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056892:Mediator Complex / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000201:enzymology*; D024510:Muscle Development; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D056892:Mediator Complex; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C510652:Kmt2c protein, mouse; C530816:MLL4 protein, human; C516439:MLL4 protein, mouse; D004257:DNA Polymerase II
keywords: H3K27ac; H3K4me1; KMT2D; MLL4; adipogenesis; cell differentiation; enhancer activation; enhancer chromatin modification; myogenesis