title: Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition.
abstract: Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ji-Eun
authors.identifier: 0000-0002-3768-7016
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Binbin
authors.initials: B
authors.lastname: Lai
authors.affiliation: Division of Developmental Biology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Todd S
authors.identifier: 0000-0003-2495-9809
authors.initials: TS
authors.lastname: Macfarlan
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Shiliyang
authors.initials: S
authors.lastname: Xu
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Lenan
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Transgenic Core, Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Physics, The George Washington University, Washington, DC 20052; Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20052.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; kai.ge@nih.gov.
authors.forename: Kai
authors.identifier: 0000-0002-7442-5138
authors.initials: K
authors.lastname: Ge
mesh_terms: D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D000066673:Cell Self Renewal / Q000235:genetics; D065150:Cellular Reprogramming; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D004268:DNA-Binding Proteins
chemical_list: D015415:Biomarkers; D050881:E1A-Associated p300 Protein; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins; C516439:MLL4 protein, mouse
keywords: H3K4 methyltransferase; MLL4/KMT2D; cell fate transition; enhancer; p300