title: MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis.
abstract: Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes in cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors (EBF2, C/EBPβ, C/EBPα, PPARγ), coactivator MED1, RNA polymerase II, as well as epigenome (H3K4me1/2/3, H3K9me2, H3K27me3, H3K36me3, H3K27ac), transcriptome and chromatin opening during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during adipogenesis. Further, MLL4 and CBP identify super-enhancers (SEs) of adipogenesis and that MLL3/MLL4 are required for SE formation. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed SEs of genes fully activated in BAT such as Ucp1. Comparison of MLL4-defined SEs in brown and white adipogenesis identifies brown-specific SE-associated genes that could be involved in BAT functions. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis.
authors.affiliation: Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.|Department of Physics and Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20052, USA.
authors.forename: Binbin
authors.initials: B
authors.lastname: Lai
authors.affiliation: Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physics and Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20052, USA.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.affiliation: Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
mesh_terms: D052437:Adipocytes, Brown / Q000502:physiology; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000166:cytology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D008822:Mice, Transgenic; D011485:Protein Binding; D015533:Transcriptional Activation; D059467:Transcriptome; D004268:DNA-Binding Proteins
chemical_list: D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D011495:Histone-Lysine N-Methyltransferase; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins; C516439:MLL4 protein, mouse; C494364:Crebbp protein, mouse; C494361:Ep300 protein, mouse