The Trithorax Group Protein Ash2l Is Essential for Pluripotency and Maintaining Open Chromatin in Embryonic Stem Cells

Wan, Ma; Liang, Jiancong; Xiong, Yuanyan; Shi, Fang; Zhang, Yi; Lu, Weisi; He, Quanyuan; Yang, Dong; Chen, Rui; Liú, Dan; Barton, Michelle C.; Songyang, Zhou

doi:10.1074/jbc.m112.424515

Cited by 69 publications

(59 citation statements)

References 66 publications

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“…S3). In contrast to a recent report on Ash2l in ESCs (Wan et al, 2013), ~10,000 TSS promoters enriched for Ash2l were observed. These strongly correlated with Mll2 sites (88%) and CpG islands (84%), indicating that Ash2l was also localised at most Mll2-occupied TSSs.…”

Section: Characterisation Of Mll2 Binding Sites In the Esc Genomecontrasting

confidence: 49%

Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant

et al. 2014

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Trimethylation of histone H3 lysine 4 (H3K4me3) at the promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax group action. Here, we show that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells. Mll2 is bound to bivalent promoters but also to most active promoters, which do not require Mll2 for H3K4me3 or mRNA expression. By contrast, the Set1 complex (Set1C) subunit Cxxc1 is primarily bound to active but not bivalent promoters. This indicates that bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4 methyltransferase, including Set1C. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed, indicating functional backup between these enzymes. Except for a subset, loss of H3K4me3 on bivalent promoters did not prevent responsiveness to retinoic acid, thereby arguing against a priming model for bivalency. In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naïve epigenome and that Polycomb group action on bivalent promoters blocks the premature establishment of active, Set1C-bound, promoters. KEY WORDS: Epigenetics, Epigenome, Histone methylation, Bivalent promoters, Trithorax group, Polycomb group, Kmt2 INTRODUCTIONIn eukaryotes, transcription is regulated not only by transcription factors that bind specific DNA sequences near the regulated gene, but also by post-translational modifications of the nucleosomes that surround and encompass these DNA sequences. The modifications include methylation, acetylation and mono-ubiquitylation of histone tails that project out from the core nucleosome and serve as binding sites for chromatin proteins and complexes (Bannister and Kouzarides, 2011;Suganuma and Workman, 2011). In vertebrates, nucleosome modifications, together with cytosine methylation, influence transcriptional regulation during development, adult life (h.stunnenberg@ncmls.ru.nl; stewart@biotec.tu-dresden.de) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. RESEARCH ARTICLE STEM CELLS AND REGENERATION Received 20 August 2013; Accepted 17 November 2013and disease (Albert and Helin, 2010;Butler et al., 2012;Reik, 2007). This epigenetic level of transcriptional regulation is crucial to the multiple ways in which a genome is interpreted in multicellular organisms (Goldberg et al., 2007).Metazoan development is regulated by programmed transcriptional hierarchies acting in synergy with epigenetic mechanisms (Fisher and Fisher, 2011; Jaenisch and Bird, 2003;Magnúsdóttir et al., 2012). The first clues about how epigenetic mechanisms regulate gene expression were discovered in Drosophila thro...

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Section: Characterisation Of Mll2 Binding Sites In the Esc Genomecontrasting

confidence: 49%

Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant

et al. 2014

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“…Importantly, we demonstrated a novel endogenous interaction between UTX and RAR and determined that this confers target gene specificity and gives a physiological significance to the physical association between the H3K27 demethylase UTX and the MLL3/4-containing H3K4 methyltransferase complexes in the regulation of gene expression, as previously reported (1,2). In particular, the trithorax protein ASH2L is considered one of the core subunits of all known H3K4-specific MLL/SET methyltransferase complexes (15), functions as an oncoprotein that is overexpressed in human tumors (27), and is essential for pluripotency in ES cells (28). NCoA6, which is essential for nuclear receptor function in vivo, is amplified and overexpressed in various human cancers (29).…”

Section: Discussionmentioning

confidence: 96%

Role of UTX in Retinoic Acid Receptor-Mediated Gene Regulation in Leukemia

Rocha-Viegas

Villa

Gutiérrez

et al. 2014

Molecular and Cellular Biology

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Human UTX, a member of the Jumonji C family of proteins, associates with mixed-lineage leukemia 3/4 complexes. Stimulation with retinoic acid leads to the recruitment of UTX-containing complexes to HOX genes, which results in demethylation of histone H3 lysine 27 and concomitant methylation of histone H3 lysine 4. Here, we show that UTX interacts with the retinoic acid receptor ␣ (RAR␣) and that this interaction is essential for proper differentiation of leukemic U937 cells in response to retinoic acid. UTX occupies the promoters of several RAR target genes and regulates their transcriptional output by modulating ASH2L complex recruitment. Overexpression of UTX in promyelocytic NB4 cells results in enhanced cellular differentiation upon retinoic acid treatment. Our results show that UTX is important for RAR-mediated transcription and provide insight into the critical role of cross talk between histone H3 lysine 4 methylation and histone H3 lysine 27 demethylation during cellular differentiation.

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“…Genome-wide assessment of Wdr5 and Oct4 indicated that they cooccupy a subset of gene promoters together with Rbbp5, Sox2, and Nanog, providing a possible molecular mechanism by which Wdr5 is necessary for ESC self-renewal (124). Depletion of Ash2l also downregulates the expression of several pluripotency factors, concomitant with the upregulation of differentiation-associated genes of all three germ layers, resulting in a loss of ESC self-renewal (126).…”

Section: Set1a/b and Mll Complexes In Escsmentioning

confidence: 99%

Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

Morey

Santanach

Croce

2015

Molecular and Cellular Biology

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c Embryonic stem cells (ESCs) are characterized by their ability to self-renew and to differentiate into all cell types of a given organism. Understanding the molecular mechanisms that govern the ESC state is of great interest not only for basic research-for instance, ESCs represent a perfect system to study cellular differentiation in vitro-but also for their potential implications in human health, as these mechanisms are likewise involved in cancer progression and could be exploited in regenerative medicine. In this minireview, we focus on the latest insights into the molecular mechanisms mediated by the pluripotency factors as well as their roles during differentiation. We also discuss recent advances in understanding the function of the epigenetic regulators, Polycomb and MLL complexes, in ESC biology. Within 2 days after fertilization, a mouse oocyte has undergone a series of cellular divisions and has developed into the morula embryo. The totipotent cells within the morula then divide and further specialize to form the hollow blastocyst sphere. The outer layer of the blastocyst contains the trophectoderm cells, while the inner cell mass (ICM) contains the pluripotent embryonic stem cells (ESCs) that will give rise in the developing embryo to all cell types of the three germ layers-ectoderm, mesoderm, and endoderm. Mouse ESCs were first isolated by Evans and Kaufman in 1981 (1) and have since been extensively studied. Under proper cell culture conditions, ESCs can divide and self-renew indefinitely, yet under differentiation stimuli, ESCs can also differentiate into virtually all cell types of the organism.Which molecular mechanisms control the decision of ESCs to self-renew or to differentiate? During the last decades, several transcription factors have been identified to be essential for ESC pluripotency. These transcription factors regulate pluripotency by a so-called "pluripotency network" that regulates their own expression and coregulates the expression of other key transcription factors through multiple mechanisms. Interestingly, pluripotency is controlled at the transcriptional levels of genes through specific signaling pathways and epigenetic factors.Epigenetics is the study of heritable changes in gene expression that are not caused by changes at the DNA sequence level. The Polycomb and MLL (myeloid-lineage leukemia) complexes are two of the best-characterized epigenetic machineries implicated in ESC pluripotency and differentiation. Although pluripotency factors do not physically interact with Polycomb and MLL complexes, they coregulate lineage-specific genes important for ESC differentiation.In this review, we discuss the most recent advances in understanding mouse ESC pluripotency and differentiation, paying particular attention to Oct4, Nanog, and Sox2, as well as to factors involved in the exit from pluripotency. Finally, we discuss the function and the molecular mechanisms of the Polycomb and MLL complexes in mouse ESC pluripotency. MASTER REGULATORS OF ESC IDENTITY: THE Oct4, Sox2, AND Nano...

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The Trithorax Group Protein Ash2l Is Essential for Pluripotency and Maintaining Open Chromatin in Embryonic Stem Cells

Abstract: Background:The trithorax protein Ash2l is a core component of the MLL complex essential for H3K4 methylation and mouse embryonic development. Results: Ash2l depletion promotes differentiation and chromatin compaction.

Cited by 69 publications

References 66 publications

Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant

Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant

Role of UTX in Retinoic Acid Receptor-Mediated Gene Regulation in Leukemia

Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

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