EZH1 Mediates Methylation on Histone H3 Lysine 27 and Complements EZH2 in Maintaining Stem Cell Identity and Executing Pluripotency

Shen, Xiaohua; Liu, Yingchun; Hsu, Yu Jung; Fujiwara, Yuko; Kim, Jonghwan; Mao, Xiaohong; Yuan, Guo Cheng; Orkin, Stuart H.

doi:10.1016/j.molcel.2008.10.016

Cited by 867 publications

(991 citation statements)

References 48 publications

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“…Chromatin condensation and the resulting gene silencing play a key role in differentiation. A hallmark for transcriptional silencing is trimethylation of lysine27 on histone H3 (H3K27me3), a process that is catalyzed by the methyl transferase activity of the Polycomb complex PCR2 (Vire et al 2006;Shen et al 2008) and antagonized by the demethylases UTX and JMJD3 (Agger et al 2007;De Santa et al 2007;Lan et al 2007;Lee et al 2007). The group of tissue-specifically repressed genes we present in this paper is expressed in embryonic stem cells and is distinct from the genes associated with Polycomb complexes in embryonic stem (ES) cells (Boyer et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

Thorrez¹,

Laudadio²,

Deun³

et al. 2010

Genome Res.

180

206

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We report on a hitherto poorly characterized class of genes that are expressed in all tissues, except in one. Often, these genes have been classified as housekeeping genes, based on their nearly ubiquitous expression. However, the specific repression in one tissue defines a special class of “disallowed genes.” In this paper, we used the intersection-union test to screen for such genes in a multi-tissue panel of genome-wide mRNA expression data. We propose that disallowed genes need to be repressed in the specific target tissue to ensure correct tissue function. We provide mechanistic data of repression with two metabolic examples, exercise-induced inappropriate insulin release and interference with ketogenesis in liver. Developmentally, this repression is established during tissue maturation in the early postnatal period involving epigenetic changes in histone methylation. In addition, tissue-specific expression of microRNAs can further diminish these repressed mRNAs. Together, we provide a systematic analysis of tissue-specific repression of housekeeping genes, a phenomenon that has not been studied so far on a genome-wide basis and, when perturbed, can lead to human disease.

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Section: Discussionmentioning

confidence: 99%

Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

Thorrez¹,

Laudadio²,

Deun³

et al. 2010

Genome Res.

180

206

View full text Add to dashboard Cite

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“…An intriguing candidate is the histone H3 lysine 27 methyltransferase EZH2. This enzyme, together with its closely related paralog EZH1, is critical for stem cell identity and for the establishment of H3K27 methylation marks within bivalent chromatin structures of embryonic stem cells (Shen et al, 2008). Several studies have described overexpression of EZH2 in human cancers, including prostate and breast cancer, as well as in lymphoma (Varambally et al, 2002;Simon and Lange, 2008).…”

Section: Epigenetic Side Effects Of Global Dna Demethylationmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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“…Une étude de phase I utilisant la molécule GSK126 a été lancée en avril 2014 chez des patients atteints de lymphomes B. Enfin, une autre étude clinique de phase I portant sur la molécule CPI-1205 dont la structure moléculaire n'a pas encore été dévoilée, a été initiée en 2015 chez des patients atteints de lymphomes B. 4 Tumeur agressive de l'enfant qui se développe généralement dans les reins. …”

Section: Rôle Suppresseur De Tumeur D'ezh2unclassified

“…EZH2 est une protéine clé du complexe PRC2 : elle porte l'activité catalytique du complexe et joue un rôle majeur dans la répression transcriptionnelle. EZH2 est la seule protéine du complexe PRC2 à posséder un paralogue connu, appelé EZH1, qui présente des fonctions partiellement redondantes, notamment dans le maintien de l'identité des cellules souches [4,45] …”

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Au cœur d’une complexité biologique

2017

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> Les protéines du groupe Polycomb (PcG) sont des facteurs épigénétiques répresseurs dont les modes de recrutement et d'action sont l'objet de nombreuses études qui viennent renverser les modèles établis. De nouvelles données montrent en effet que le recrutement de ces protéines a un caractère dynamique qui n'apparaissait pas dans le modèle hiérarchique initial. Des études dévoilent également qu'EZH2, une protéine clé des PcG, peut être associée à une chromatine permissive à la transcription, défiant la fonction de répresseur transcriptionnel des protéines PcG. Le double rôle d'EZH2, qui se comporte comme un oncogène ou un suppresseur de tumeur en fonction du type cellulaire, illustre ainsi la complexité des fonctions de ces protéines. < À ce jour, trois complexes PcG associant différentes protéines ont été identifiés : PhoRC (Pho [pleiohomeotic] repressive complex), PRC1 et PRC2 (polycomb repressive complex 1 and 2) (Figure 1). On distingue plusieurs complexes PRC1 constitués de différentes sousunités, chacune pouvant elle-même avoir plusieurs paralogues. Quel que soit le complexe, l'unité catalytique de PRC1 est portée par l'une ou l'autre des protéines RING1A ou RING1B (really interesting new gene) qui catalysent l'ajout d'une ubiquitine sur la lysine située en position 119 de l'histone H2A (H2AK119ub1) [2]. Les principales protéines composant le complexe PRC2 sont, quant à elles, au nombre de trois : EZH2 (enhancer of zeste homologue 2), EED (embryonic ectoderm development) et SUZ12 (suppressor of zeste 12). L'association de ces trois sous-unités est nécessaire à l'activité catalytique d'EZH2 qui est responsable de la mono-, di-ou triméthylation de la lysine située en position 27 de l'histone H3 (H3K27me1, 2 ou 3) [3]. EZH2 est une protéine clé du complexe PRC2 : elle porte l'activité catalytique du complexe et joue un rôle majeur dans la répression transcriptionnelle. EZH2 est la seule protéine du complexe PRC2 à posséder un paralogue connu, appelé EZH1, qui présente des fonctions partiellement redondantes, notamment dans le maintien de l'identité des cellules souches [4,45]

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EZH1 Mediates Methylation on Histone H3 Lysine 27 and Complements EZH2 in Maintaining Stem Cell Identity and Executing Pluripotency

Cited by 867 publications

References 48 publications

Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

Epigenetic cancer therapy: rationales, targets and drugs

Au cœur d’une complexité biologique

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