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

Ji-Eun Lee; Chaochen Wang; Shiliyang Xu; Young-Wook Cho; Lifeng Wang; Xuesong Feng; Vittorio Sartorelli; Anne Baldridge; Weiqun Peng; Kai Ge

arXiv · 1311.7328

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

Ji-Eun Lee·Chaochen Wang·Shiliyang Xu·Young-Wook Cho·Lifeng Wang·Xuesong Feng·Vittorio Sartorelli·Anne Baldridge·Weiqun Peng·Kai Ge

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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. Here 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, Polymerase II and Mediator 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.

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Ji-Eun Lee, Chaochen Wang, Shiliyang Xu, Young-Wook Cho, Lifeng Wang, Xuesong Feng, Vittorio Sartorelli, Anne Baldridge, Weiqun Peng, Kai Ge. 2013-11-28. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. https://arxiv.org/abs/1311.7328

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