The Murine Polycomb Group Protein Eed Is Required for Global Histone H3 Lysine-27 Methylation

Montgomery, Nathan D.; Yee, Della; Chen, Andrew; Kalantry, Sundeep; Chamberlain, Stormy J.; Otte, Arie P.; Magnuson, Terry

doi:10.1016/j.cub.2005.04.051

Cited by 321 publications

(281 citation statements)

References 20 publications

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“…Total histone H3 levels were used as a loading control. (12,41). Previous studies have also shown that, although it contains the Su(var)3-9, enhancer of zeste, and trithorax domain for HMTase activity for H3K27, to gain catalytic activity EZH2 requires association with SUZ12 and EED (41).…”

Section: Discussionmentioning

confidence: 99%

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Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Fiskus¹,

Pranpat²,

Balasis³

et al. 2006

Molecular Cancer Therapeutics

102

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Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes.

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Section: Discussionmentioning

confidence: 99%

“…Besides its catalytic HMTase domain, EZH2 contains highly conserved NH 2 -terminal protein interaction domains responsible for binding to EED and a nuclear localization domain (11). EED recruits HDAC activity to the PRC2 complex (12).…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Fiskus¹,

Pranpat²,

Balasis³

et al. 2006

Molecular Cancer Therapeutics

102

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“…Ezh2 exhibits methytransferase activity mainly through methylating lysine 27 on the histone 3 (H3K27). As a consequence some genes associated with tumor inhibition and stem cell differentiation are silenced (Cao et al, 2004;Montgomery et al, 2005). In mammals, two E(z)-related genes have been isolated, Ezh1 and Ezh2.…”

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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“…Mouse ESC lines wild-type E14 (ola/129) and Eed-/-were grown on MEFs. Eed-/-ESCs were described previously 44 .…”

Section: Methodsmentioning

confidence: 99%

“…We next tested whether PRC2 is required for HEB binding at developmental promoters. To this end, we examined HEB occupancy in Eed homozygous mutant (Eed-/-) ESCs, which have disruption of PRC2-mediated H3K27 methylation, but can maintain ESC pluripotency on mouse embryonic fibroblasts (MEFs) 7,25,26,35,44 ( Supplementary Fig. 8a,b).…”

Section: Heb Occupies Bivalent Domainsmentioning

confidence: 99%

HEB associates with PRC2 and SMAD2/3 to regulate developmental fates

2015

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In embryonic stem cells, extracellular signals are required to derepress developmental promoters to drive lineage specification, but the proteins involved in connecting extrinsic cues to relaxation of chromatin remain unknown. We demonstrate that the helix-loop-helix (HLH) protein, HEB, directly associates with the Polycomb repressive complex 2 (PRC2) at a subset of developmental promoters, including at genes involved in mesoderm and endoderm specification and at the Hox and Fox gene families. While we show that depletion of HEB does not affect mouse ESCs, it does cause premature differentiation after exposure to Activin. Further, we find that HEB deposition at developmental promoters is dependent upon PRC2 and independent of Nodal, whereas HEB association with SMAD2/3 elements is dependent of Nodal, but independent of PRC2. We suggest that HEB is a fundamental link between Nodal signalling, the derepression of a specific class of poised promoters during differentiation, and lineage specification in mouse ESCs.

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The Murine Polycomb Group Protein Eed Is Required for Global Histone H3 Lysine-27 Methylation

Cited by 321 publications

References 20 publications

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

The Expression Pattern of Polycomb Group Protein Ezh2 During Mouse Embryogenesis

HEB associates with PRC2 and SMAD2/3 to regulate developmental fates

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