Ezh1 and Ezh2 Maintain Repressive Chromatin through Different Mechanisms

Margueron, Raphaël; Li, Guohong; Sarma, Kavitha; Blais, Alexandre; Zavadil, Jiří; Woodcock, Christopher L.; Dynlacht, Brian David; Reinberg, Danny

doi:10.1016/j.molcel.2008.11.004

Cited by 753 publications

(847 citation statements)

References 70 publications

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“…There is large overlap in the set of genes that retain H3K27me3 between ES cells and AML leukemic cells, and almost all of these genes are documented Ezh1 targets. Ezh1 is the only other known methyltransferase besides Ezh2 to catalyze the trimethylation of H3K27 (16,32). The ability of Ezh1 to compensate for Ezh2 inactivation in cancer appears to be context dependent (30).…”

Section: Discussionmentioning

confidence: 99%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

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

196

218

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A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML. epigenetics | mouse model | polycomb group proteins | myeloid-lymphoid leukemia protein P olycomb repressive complex 2 (PRC2) has been implicated in development and cancer (1, 2). PRC2 is composed of the core components embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and a SET-domain methyltransferase, either enhancer of zeste 2 (EZH2) or enhancer of zeste 1 (EZH1) (3). The PRC2 complex catalyzes the di-and trimethylation of lysine residue 27 of histone 3 (H3K27me3), a repressive chromatin mark (4). Overexpression of EZH2 has been correlated with prostate cancer progression (5). Follow-up studies have confirmed and expanded these results for other cancer types, mainly solid tumors. In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9-12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML). How to reconcile these findings on a mechanistic level is unclear. Given the heterogeneity of clinical samples, elucidating the complex role of PRC2 biology in cancer will be aided by studies in genetically defined animal models (13).Loss of function of PRC2 has been evaluated in several cancer models (14, 15). However, shRNA...

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Section: Discussionmentioning

confidence: 99%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

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

196

218

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“…Consistent with this observation, Ezh2 is required for early mouse development. The two proteins show functional complementation but don't appear to be completely redundant, since Ezh1 can't rescue the pluripotency defects observed in EZH2 À/À embryonic stem cells (Margueron et al, 2008). Ezh2 À null mouse embryos die during the transition from pre-to post-implantation development (O'Carroll et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Expression Pattern of Polycomb Group Protein Ezh2 During Mouse Embryogenesis

Zhu

Liu

et al. 2011

The Anatomical Record

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The Polycomb group (PcG) family proteins are required for the stability of homeotic selector genes and other genes related to the regulation of mammalian development through their roles in the modulation of chromatin domains. Among them, the mammalian enhancer zeste homologue 2 (Ezh2) contributes to the transcriptional repression of these genes. Previous studies tracked the Ezh2 expression at cDNA and mRNA levels during mouse development. However, little information is known about the expression patterns of Ezh2 at the protein levels. In this study, the embryos (E6.5-E18.5) obtained through timed matings of strain Kunming mice were inserted into paraffin blocks. Tissue microarrays were constructed and followed by subsequent immunohistochemical staining. The positive cells were identified and scored based on both the percentage of stained cells and their staining intensities. Ezh2 protein expression was found throughout the embryonic tissues including the nerves, intestine epithelial, liver, pancreas, renal tubule, and lungs. Its expression level was higher at early embryonic developmental stages. However, the nerve fibers and myocardium showed weak or no immunostaining reactivities. Ezh2 protein was moderately expressed in the nuclei of renal tubule epithelial cells at E14.5. In contrast, it was weakly expressed in the fetal kidneys at E18.5 and the protein was localized in the cytoplasm of the renal tubule epithelial cells. Our data confirmed that Ezh2 protein was expressed in mouse embryos and its expression exhibited tissue specificity and dependence on the stages of embryo development. thus providing new information helpful for understanding the possible roles of Ezh2 in embryogenesis. Anat Rec, 294:1150Rec, 294: -1157Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

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“…A schematic representation of the components of PRC1 and PRC2 is illustrated in Figure 1. The main components of PRC1 and PRC2 in Drosophila, mouse and human are summarized in Table 1 (Laible et al, 1999;O'Carroll et al, 2001;Margueron et al, 2008) Ezh1 and Ezh2 (Margueron et al, 2008) SET domain, CXC domain and homology domains I and II…”

Section: Components Of Polycomb Complexesmentioning

confidence: 99%

“…DNA-binding factors and CpG islands are two main features involved in the recruitment of Pc complexes to chromatin, particularly on PREs (Gal-Yam et al, 2008;Meissner et al, 2008;Mendenhall et al, 2010). Nucleosomal array analyses have shown that Pc components are able to remodel chromatin structure and compact chromatin independently of histone modifications (Eskeland et al, 2010;Francis et al, 2004;Margueron et al, 2008). PRC1 inhibits transcription at the promoter region of the targeted gene through chromatin remodeling (Lavigne et al, 2004), although this conclusion is controversial (Eskeland et al, 2010).…”

Section: Recruitment Of Polycomb Complexesmentioning

confidence: 99%

Gene Silencing and Polycomb Group Proteins: An Overview of their Structure, Mechanisms and Phylogenetics

Golbabapour

Majid²,

Hassandarvish³

et al. 2013

OMICS: A Journal of Integrative Biology

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DNA methylation, histone modifications, and chromatin configuration are crucially important in the regulation of gene expression. Among these epigenetic mechanisms, silencing the expression of certain genes depending on developmental stage and tissue specificity is a key repressive system in genome programming. Polycomb (Pc) proteins play roles in gene silencing through different mechanisms. These proteins act in complexes and govern the histone methylation profiles of a large number of genes that regulate various cellular pathways. This review focuses on two main Pc complexes, Pc repressive complexes 1 and 2, and their phylogenetic relationship, structures, and function. The dynamic roles of these complexes in silencing will be discussed herein, with a focus on the recruitment of Pc complexes to target genes and the key factors involved in their recruitment.

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Ezh1 and Ezh2 Maintain Repressive Chromatin through Different Mechanisms

Cited by 753 publications

References 70 publications

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

The Expression Pattern of Polycomb Group Protein Ezh2 During Mouse Embryogenesis

Gene Silencing and Polycomb Group Proteins: An Overview of their Structure, Mechanisms and Phylogenetics

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