Role of <scp>PRC</scp>2‐associated factors in stem cells and disease

Vizán, Pedro; Beringer, Malte; Ballaré, Cecilia; Croce, Luciano Di

doi:10.1111/febs.13083

Cited by 69 publications

(75 citation statements)

References 94 publications

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“…The PRC2 complex architecture is not as heterogeneous as the PRC1 complex (Fig. 2), yet several cofactors have recently been identified that associate it with PRC2 members in ESCs (92). In the past years, the Jumanji protein Jarid2 was identified as the first protein to interact directly, via its interaction with Suz12, with the core PRC2 complex in ESCs.…”

Section: Do These Complexes Have Redundant Functions In Escs?mentioning

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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Section: Do These Complexes Have Redundant Functions In Escs?mentioning

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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“…Several lines of evidence suggest that EZH2 deregulation is an important driver of cancer development and progression and that inactivation of EZH2 may be therapeutically effective in many cancers [4,5,11,12,73,[76][77][78][79][80][81][82][83][84][85][86][87][88][89] . EZH2 is highly expressed in a wide range of cancer types, including lung, breast, colon, prostate, bladder and pancreatic cancer, as well as sarcomas and lymphomas [4,5,11,12,76,77,80,82,83,[85][86][87][88] . Correspondingly, overexpression of EZH2 often correlates with advanced stages of human cancer progression and poor prognosis [4,12,76] .…”

Section: Prc2 and Diseasesmentioning

confidence: 99%

Structure of the PRC2 complex and application to drug discovery

et al. 2017

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The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery.

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“…Cette étude (NCT01897571) initiée en 2013, devrait se terminer en 2020. Cependant, des résultats préliminaires montrent qu'une réponse partielle ou totale a pu être observée chez 9 des 15 patients atteints de lymphomes non-hodgkiniens 5 . Les molécules GSK126 et EI1 sont actives à la fois sur les deux formes d'EZH2.…”

Section: Rôle Suppresseur De Tumeur D'ezh2unclassified

“…Elles augmentent son activité catalytique ou modifient son adressage et sa liaison à la chromatine. C'est, par exemple, le cas du facteur chromatinien JARID2 (Jumonji and ATrich interaction domain containing 2) capable de se lier à l'ADN et d'induire l'adressage du complexe PRC2 à la chromatine [5]. Les protéines du groupe Polycomb (PcG) sont des facteurs épigénétiques qui ont été initialement décou-verts chez la drosophile pour leur implication dans la répression des gènes Hox au cours du développement 1 .…”

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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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Role of PRC2‐associated factors in stem cells and disease

Cited by 69 publications

References 94 publications

Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

Structure of the PRC2 complex and application to drug discovery

Au cœur d’une complexité biologique

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