H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation

被引:391
作者
Lee, Ji-Eun [1 ]
Wang, Chaochen [1 ]
Xu, Shiliyang [1 ,2 ]
Cho, Young-Wook [1 ,3 ]
Wang, Lifeng [1 ]
Feng, Xuesong [4 ]
Baldridge, Anne [1 ]
Sartorelli, Vittorio [4 ]
Zhuang, Lenan [1 ]
Peng, Weiqun [2 ,5 ]
Ge, Kai [1 ]
机构
[1] NIDDK, Adipocyte Biol & Gene Regulat Sect, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA
[2] George Washington Univ, Dept Phys, Washington, DC 20052 USA
[3] Korea Basic Sci Inst, Chuncheon Ctr, Chunchon, South Korea
[4] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA
[5] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC USA
基金
美国国家卫生研究院;
关键词
HISTONE-MODIFYING GENES; EMBRYONIC STEM-CELLS; PPAR-GAMMA; TRANSCRIPTION FACTORS; HUMAN GENOME; LYSINE; ADIPOGENESIS; EXPRESSION; IDENTIFICATION; METHYLATION;
D O I
10.7554/eLife.01503
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:25
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