RESUMEN
The Polycomb repressive complex 2 (PRC2) is a conserved chromatin-remodelling complex that catalyses the trimethylation of histone H3 lysine 27 (H3K27me3), a mark associated with gene silencing. PRC2 regulates chromatin structure and gene expression during organismal and tissue development and tissue homeostasis in the adult. PRC2 core subunits are associated with various accessory proteins that modulate its function and recruitment to target genes. The multimeric composition of accessory proteins results in two distinct variant complexes of PRC2, PRC2.1 and PRC2.2. Metal response element-binding transcription factor 2 (MTF2) is one of the Polycomb-like proteins (PCLs) that forms the PRC2.1 complex. MTF2 is highly conserved, and as an accessory subunit of PRC2, it has important roles in embryonic stem cell self-renewal and differentiation, development, and cancer progression. Here, we review the impact of MTF2 in PRC2 complex assembly, catalytic activity, and spatiotemporal function. The emerging paradoxical evidence suggesting that MTF2 has divergent roles as either a tumour suppressor or an oncogene in different tissues merits further investigations. Altogether, our review illuminates the context-dependent roles of MTF2 in Polycomb group (PcG) protein-mediated epigenetic regulation. Its impact on disease paves the way for a deeper understanding of epigenetic regulation and novel therapeutic strategies.
Asunto(s)
Proteínas de Drosophila , Histonas , Animales , Humanos , Cromatina , Proteínas de Drosophila/genética , Epigénesis Genética , Histonas/genética , Histonas/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Unión ProteicaRESUMEN
Polycomb-like proteins (PCLs) are a crucial group of proteins associated with the Polycomb repressive complex 2 (PRC2) and are responsible for setting up the PRC2.1 subcomplex. In the vertebrate system, three homologous PCLs exist: PHF1 (PCL1), MTF2 (PCL2), and PHF19 (PCL3). Although the PCLs share a similar domain composition, they differ significantly in their primary sequence. PCLs play a critical role in targeting PRC2.1 to its genomic targets and regulating the functionality of PRC2. However, they also have PRC2-independent functions. In addition to their physiological roles, their dysregulation has been associated with various human cancers. In this review, we summarize the current understanding of the molecular mechanisms of the PCLs and how alterations in their functionality contribute to cancer development. We particularly highlight the nonoverlapping and partially opposing roles of the three PCLs in human cancer. Our review provides important insights into the biological significance of the PCLs and their potential as therapeutic targets for cancer treatment.
Asunto(s)
Proteínas de Drosophila , Neoplasias , Humanos , Histonas/genética , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Complejo Represivo Polycomb 2/genética , Núcleo Celular/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Proteínas de Drosophila/metabolismo , Neoplasias/genéticaRESUMEN
Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is thought to recruit canonical PRC1 (cPRC1) via chromodomain-containing CBX proteins to promote stable repression of developmental genes. PRC2 forms two major subcomplexes, PRC2.1 and PRC2.2, but their specific roles remain unclear. Through genetic knockout (KO) and replacement of PRC2 subcomplex-specific subunits in naïve and primed pluripotent cells, we uncover distinct roles for PRC2.1 and PRC2.2 in mediating the recruitment of different forms of cPRC1. PRC2.1 catalyzes the majority of H3K27me3 at Polycomb target genes and is sufficient to promote recruitment of CBX2/4-cPRC1 but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at catalyzing H3K27me3, we find that its accessory protein JARID2 is essential for recruitment of CBX7-cPRC1 and the consequent 3D chromatin interactions at Polycomb target genes. We therefore define distinct contributions of PRC2.1- and PRC2.2-specific accessory proteins to Polycomb-mediated repression and uncover a new mechanism for cPRC1 recruitment.
Asunto(s)
Histonas , Complejo Represivo Polycomb 2 , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Histonas/genética , Histonas/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Cromatina/genéticaRESUMEN
Diverse accessory subunits are involved in the recruitment of polycomb repressive complex 2 (PRC2) to CpG island (CGI) chromatin. Here we report the crystal structure of a SUZ12-RBBP4 complex bound to fragments of the accessory subunits PHF19 and JARID2. Unexpectedly, this complex adopts a dimeric structural architecture, accounting for PRC2 self-association that has long been implicated. The intrinsic PRC2 dimer is formed via domain swapping involving RBBP4 and the unique C2 domain of SUZ12. MTF2 and PHF19 associate with PRC2 at around the dimer interface and stabilize the dimer. Conversely, AEBP2 binding results in a drastic movement of the C2 domain, disrupting the intrinsic PRC2 dimer. PRC2 dimerization enhances CGI DNA binding by PCLs in pairs in vitro, reminiscent of the widespread phenomenon of transcription factor dimerization in active transcription. Loss of PRC2 dimerization impairs histone H3K27 trimethylation (H3K27me3) on chromatin at developmental gene loci in mouse embryonic stem cells.
Asunto(s)
Cromatina/metabolismo , Islas de CpG , Metilación de ADN , Histonas/metabolismo , Complejo Represivo Polycomb 2/química , Multimerización de Proteína , Animales , Diferenciación Celular , Cromatina/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Histonas/genética , Humanos , Ratones , Ratones Noqueados , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Proteínas de Neoplasias , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/fisiología , Conformación Proteica , Proteína 4 de Unión a Retinoblastoma/genética , Proteína 4 de Unión a Retinoblastoma/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Polycomb repressive complex 2 (PRC2) is composed of EED, SUZ12, and EZH1/2 and mediates mono-, di-, and trimethylation of histone H3 at lysine 27. At least two independent subcomplexes exist, defined by their specific accessory proteins: PRC2.1 (PCL1-3, EPOP, and PALI1/2) and PRC2.2 (AEBP2 and JARID2). We show that PRC2.1 and PRC2.2 share the majority of target genes in mouse embryonic stem cells. The loss of PCL1-3 is sufficient to evict PRC2.1 from Polycomb target genes but only leads to a partial reduction of PRC2.2 and H3K27me3. Conversely, disruption of PRC2.2 function through the loss of either JARID2 or RING1A/B is insufficient to completely disrupt targeting of SUZ12 by PCLs. Instead, the combined loss of both PRC2.1 and PRC2.2 is required, leading to the global mislocalization of SUZ12. This supports a model in which the specific accessory proteins within PRC2.1 and PRC2.2 cooperate to direct H3K27me3 via both synergistic and independent mechanisms.
Asunto(s)
Cromatina/metabolismo , Histonas/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Sitios de Unión , Línea Celular Tumoral , Cromatina/genética , Humanos , Metilación , Ratones , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 2/genética , Unión Proteica , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoAsunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo Polycomb/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Puntos de Control del Ciclo Celular , Proteínas de Unión al ADN/química , Humanos , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Proteínas del Grupo Polycomb/química , Estructura Terciaria de Proteína , Proteína p53 Supresora de Tumor/químicaRESUMEN
Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation. We show that while PCL2 and PCL3 are E2F-regulated genes expressed in proliferating cells, PCL1 is a p53 target gene predominantly expressed in quiescent cells. Ectopic expression of any PCL protein recruits PRC2 to repress the INK4A gene; however, only PCL2 and PCL3 confer an INK4A-dependent proliferative advantage. Remarkably, PCL1 has evolved a PRC2- and chromatin-independent function to negatively regulate proliferation. We show that PCL1 binds to and stabilizes p53 to induce cellular quiescence. Moreover, depletion of PCL1 phenocopies the defects in maintaining cellular quiescence associated with p53 loss. This newly evolved function is achieved by the binding of the PCL1 N-terminal PHD domain to the C-terminal domain of p53 through two unique serine residues, which were acquired during recent vertebrate evolution. This study illustrates the functional bifurcation of PCL proteins, which act in both a chromatin-dependent and a chromatin-independent manner to regulate the INK4A and p53 pathways.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas del Grupo Polycomb/metabolismo , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proliferación Celular/genética , Células Cultivadas , Cromatina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteínas de Unión al ADN/genética , Factores de Transcripción E2F/metabolismo , Humanos , Ratones , Proteínas del Grupo Polycomb/genética , Unión Proteica , Estabilidad Proteica , Estructura Terciaria de Proteína/genéticaRESUMEN
The Polycomb group (PcG) of proteins form chromatin-binding complexes with histone-modifying activity. The two main PcG repressive complexes studied (PRC1 and PRC2) are generally associated with chromatin in its repressed state. PRC2 is responsible for methylation of histone H3 at lysine 27 (H3K27me3), an epigenetic mark that is linked with numerous biological processes, including development, adult homeostasis and cancer. The core canonical complex PRC2, which contains the EZH1/2, SUZ12 and EED proteins, may be extended and functionally manipulated through interactions with several other proteins. In this review, we focus on these PRC2-associated proteins. As PRC2 functions are diverse, the variability conferred by these sub-stoichiometrically associated members may help to understand specific changes in PRC2 activity, chromatin recruitment and distribution required for gene repression.