Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Rao, Rajesh C.; Dou, Yali

doi:10.1038/nrc3929

Cited by 523 publications

(584 citation statements)

References 197 publications

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“…MLL4 and its homolog MLL3 have been shown to function as tumor supressors and are frequently mutated in many types of cancers and developmental diseases (24,25). Our findings suggest that loss-of-function mutations in MLL3/MLL4 would prevent the activation of de novo enhancers and the induction of cell-type-specific genes, leading to defects in cell fate transition.…”

Section: Mll4 Is Dispensable For Maintaining Somatic Cell Identity Butmentioning

confidence: 75%

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Wang

Lee

Lai

et al. 2016

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

189

188

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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: Mll4 Is Dispensable For Maintaining Somatic Cell Identity Butmentioning

confidence: 75%

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Wang

Lee

Lai

et al. 2016

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

189

188

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“…The mixed lineage leukaemia (MLL) gene encodes a histone methylating enzyme (KMT2A) that functions as an epigenetic regulator. The MLL locus is highly susceptible to breakage and rearrangement, this can generate oncogenic MLL fusion proteins which lack methyltransferase activity 85 . Rearrangements in MLL are recurrent oncogenic drivers in a variety of leukaemias including acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL) 86 .…”

Section: Failed Apoptosis and Cancermentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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“…The amino terminus of MLL1 interacts with menin, a critical interaction for the MLLfusion protein function. This is followed by three AT-hook domains that can bind to the minor grove of DNA and a CXXC domain that binds to unmethylated CpGs (Rao and Dou 2015). The CXXC domain is followed by a set of domains that can interact with modified histone tails and includes four plant homology domains (PHDs) and a bromodomain (BRD).…”

Section: Structure Of the Mll/kmt2 Familymentioning

confidence: 99%

“…In fact, inclusion of PHDs within the MLL fusions negates the transformation activity of these fusions (Muntean et al 2008). Full-length MLL1 is cleaved by Taspase1 and reassembled through interaction of FYRN with FYRC domains (Rao and Dou 2015). For almost a decade, studies were unable to show enzymatic activity of MLL1 (Rea et al 2000).…”

Section: Structure Of the Mll/kmt2 Familymentioning

confidence: 99%

“…Later, it was established that the SET domain of MLL1 can catalyze monomethyl and dimethyl and to lesser extent the trimethyl modification of H3K4 (Wu et al 2013). These studies showed enzymatic activity of the SET domain, but we now know that the full MLL1 complex is required to support efficient modification of H3K4 (Rao and Dou 2015). Genome-scale occupancy studies using chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed association of MLL1 with a subset of active promoters Wang et al 2009) as well as certain enhancers (Wang et al 2011;Yang et al 2014).…”

Section: Structure Of the Mll/kmt2 Familymentioning

confidence: 99%

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Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

Krivtsov

Hoshii

Armstrong

2017

Cold Spring Harb Perspect Med

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Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associated complexes such as the H3K79 methyltransferase DOT1L and the super elongation complex. Therefore, chromosomal translocations involving MLL1 appear to directly perturb the regulation of multiple chromatin-associated complexes to allow inappropriate expression of developmentally regulated genes and thus drive leukemia development. IDENTIFICATION AND STRUCTURE OF MLL FUSIONS

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Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Cited by 523 publications

References 197 publications

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

A fate worse than death: apoptosis as an oncogenic process

Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

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