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

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

doi:10.7554/elife.01503

Cited by 417 publications

(657 citation statements)

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“…After filtering out nonspecific signals observed in the DKO cells (8), 12,383 high-confidence MLL4 binding sites were identified in f/f ESCs, the vast majority of which were marked by H3K4me1 and/or H3K4me2 (Fig. 1B).…”

Section: Significancementioning

confidence: 99%

“…In cultured cells, MLL3 partially compensates for the loss of MLL4 (8). To investigate the role of MLL4 in ESC self-renewal and differentiation, we derived Mll3 KO and Mll4 conditional KO (Mll3 −/− Mll4 f/f , hereafter referred to as f/f) ESCs from blastocysts.…”

Section: Mll4 Associates With Active Enhancers On Cell-identity Genesmentioning

confidence: 99%

“…MLL4 colocalizes with lineage-determining TFs on AEs during adipogenesis and myogenesis. Furthermore, MLL4 is required for enhancer activation, cell-type-specific gene expression, and cell differentiation during adipogenesis and myogenesis (8). These observations prompted us to investigate whether MLL4 plays a more general role in the control of cell fate transition and how MLL4 regulates enhancer activation.…”

mentioning

confidence: 99%

“…Differentiated somatic cells can also be converted back to the pluripotent stage by ectopic expression of Oct4 and Sox2 together with Klf4 and c-Myc, a process known as somatic cell reprogramming into induced pluripotent stem cells (iPSCs) (6). The dramatic changes of cell identity that accompany ESC differentiation and somatic cell reprogramming make these two processes excellent models for studying cell fate transition and the underlying molecular mechanism.MLL4 is a major enhancer H3K4 mono-and di-methyltransferase with partial functional redundancy with MLL3 in mammalian cells (7,8). MLL4 colocalizes with lineage-determining TFs on AEs during adipogenesis and myogenesis.…”

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confidence: 99%

“…MLL4 is a major enhancer H3K4 mono-and di-methyltransferase with partial functional redundancy with MLL3 in mammalian cells (7,8). MLL4 colocalizes with lineage-determining TFs on AEs during adipogenesis and myogenesis.…”

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confidence: 99%

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Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Wang

Lee

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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.enhancer | MLL4/KMT2D | H3K4 methyltransferase | cell fate transition | p300 I n mammalian cells, enhancers coordinate with promoters to precisely control cell-type-specific gene transcription, which determines the cell identity (1, 2). Comprehensive genome-wide studies have provided insights into the chromatin signatures of enhancers. Primed enhancers are marked by H3K4me1/2. Active enhancers (AEs) are further marked by the histone acetyltransferases CBP/p300-mediated H3K27ac (3). Recent studies classify AEs into typical enhancers and superenhancers. Superenhancers are clusters of AEs bound by lineage-determining transcription factors (TFs). Compared with typical enhancers, superenhancers are more cell-lineage-specific and control cell identity (4). Enhancer activation is orchestrated through a regulatory network involving lineage-determining TFs and chromatinmodifying complexes (2). However, how chromatin-modifying complexes regulate enhancer activation and cell fate transition is poorly understood.Embryonic stem cells (ESCs) derived from blastocysts are capable of unlimited replication in vitro, a property known as ESC self-renewal. ESC identity is maintained during self-renewal. ESC self-renewal is controlled by a core circuitry of TFs including Oct4, Sox2, and Nanog (4). ESCs can rapidly respond to environmental cues and differentiate into three germ layers-ectoderm, endoderm, and mesoderm-which consist of all cell lineages within days (5). Differentiated somatic cells can also be converted back to the pluripotent stage by ectopic expression of Oct4 and Sox2 together with Klf4 and c-Myc, a process known as somatic cell reprogramming into induced pluripotent stem cells (iPSCs) (6). The dramatic changes of ce...

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Section: Significancementioning

confidence: 99%

Section: Mll4 Associates With Active Enhancers On Cell-identity Genesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Wang

Lee

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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192

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KMT2C promoter methylation in plasma‐circulating tumor DNA is a prognostic biomarker in non‐small cell lung cancer

et al. 2020

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MLL3 histone methyltransferase, encoded by the KMT2C gene, is a tumor suppressor that has an essential role in cell type-specific gene expression. We evaluated the prognostic significance of KMT2C promoter methylation as a circulating epigenetic biomarker in plasma cell-free DNA (cfDNA) in non-small cell lung cancer (NSCLC). We examined the methylation status of KMT2C promoter using a novel highly specific and sensitive real-time methylation-specific PCR (MSP) assay in: a) operable NSCLC: 48 fresh-frozen NSCLC tissues, their corresponding adjacent nonneoplastic tissues and 48 matched plasma samples; b) metastatic NSCLC: 91 plasma samples and c) 60 plasma samples from healthy donors (HD). KMT2C promoter methylation in plasma-cfDNA was detected in 7/48 (14.6%) patients with operable and in 18/91 (19.8%) patients with advanced NSCLC but in none (0/60, 0%) of the plasma samples from HD. In operable NSCLC, in corresponding adjacent non-neoplastic tissue samples, KMT2C promoter methylation was detected in 3/48 (6.3%) cases. Moreover, in operable NSCLC, KMT2C promoter methylation in plasma-cfDNA was related to reduced disease-free survival (DFS) (ΗR=0.239; p=0.001) and worse overall survival (OS) (HR=0.342, p=0.023). In metastatic NSCLC, KMT2C promoter methylation in plasma-cfDNA was related to worse progression-free survival (PFS) (HR=0.431; p=0.005) and worse OS (HR=0.306; p<0.001). Our data strongly suggest that detection of KMT2C promoter methylation in plasma cfDNA predicts poor prognosis in patients with both operable and metastatic NSCLC. KMT2C promoter methylation in plasma cfDNA therefore merits further evaluation and validation as a non-invasive circulating epigenetic biomarker.

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