Role of polycomb proteins Ring1A and Ring1Bin the epigenetic regulation of gene expression

Abstract

Generation of cell diversity depends on epigenetic regulatory mechanisms. Polycomb group (PcG) proteins are central components of epigenetic regulation in metazoans. The system, initially associated with transcriptional program stability during development, is also involved in the regulation of other processes, such as maintenance of stem cell pluripotency and cell proliferation. PcG regulation involves chromatin modifications through covalent histone modifications. One of these modifications, the monoubiquitylation of the H2A histone, depends on Ring1 proteins, which are essential for development in insects and mammals. In murine embryonic stem cells, Ring1A and Ring1B-dependent ubiquitylation of H2A is linked to repression of transcriptional initiation. Studies in mammalian cells have found a multiplicity of protein complexes containing Ring1A and Ring1B, suggesting an expanded regulatory role for Ring1A, Ring1B proteins in the epigenetic regulation of gene expression. KEY WORDS: Ring1A, Ring1B, polycomb, H2A ubiquitylation, epigenetic regulation Ring1A/Ring1 and its paralog Ring1B/Rnf2 are core components of the mammalian Polycomb system, which is one of the epigenetic regulators of cell diversity generation during embryonic development and tissue maintenance during adult life (Rajasekhar, 2007;Sparmann, 2006). Although initially identified during genetic studies of developmental regulation of the fruit fly D. melanogaster, the Polycomb group (PcG) of genes is represented throughout all metazoans (Ringrose, 2004;Schuettengruber, 2007;Whitcomb, 2007). PcG was named after the founding member, Polycomb (Pc), a term that refers to the extra number of sexual combs found in Pc mutant fly males. During this genetic analysis of Drosophila development, another group of genes, the trithorax group (trxG) was identified because of their ability to counteract the activity of PcG genes (Ringrose, 2004;Grimaud, 2006;Schwartz, 2007).PcG genes encode subunits of multiprotein complexes with a role as transcriptional repressors (Table 1). In mammals, developmental processes controlled by PcG genes include specification of the antero-posterior axis, monoallelic expression of imprinted genes and self-renewal of embryonic and somatic stem cells. In addition, deregulation of the Polycomb system is often associated to neoplastic events and tumor formation (ValkLingbeek, 2004;Sparmann, 2006;Rajasekhar, 2007).Polycomb complexes act, at least in part, through chemical modification of histones, one of the mechanisms involved in the multilayered, interdependent, processes that regulate the selective use of the genome (Shilatifard, 2006;Taverna, 2007). Two types of postranslational modifications of histones, associated to transcriptional repression, are dependent on PcG complexes (Polycomb repressive complexes, PRCs). One of these covalent modifications, trimethylation of the lysine 27 of histone H3 (H3K27me3), is catalyzed by a histone methyltransferase and associated cofactors that appeared earliest in evolution and are foun...

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

“…However, the mechanism of Rnf2 in cancer development remains poorly understood. Previously, Rnf2 was shown to repress the transcription of p16Ink4a, which mediates Rnf2 activities in cancer cells 22,33,34). However, in the present study, Rnf2 directly degraded p53 through the proteasome pathway.…”

“…The gene regulation through PC complexes involves the trimethylation of histone H3 at lysine 27 catalyzed through the activity of PRC2 (20), which in turn recruits the PRC1 complex to chromatin to mediate histone H2A monoubiquitination (21). As the primary E3 ligase responsible for H2A modification in the PRC1 complex, Rnf2 plays important roles in both early development and ES cell maintenance (22). In addition to its monoubiquitination activity, the PRC1 complex also has poly-ubiquitination activity.…”

The Polycomb group protein Ring1b is essential for pectoral fin development

“…In addition, Ring1b can participate in several PRC1-like complexes (Gao et al, 2012) and PRC1 can be found at chromatin independently of PRC2 (Trojer et al, 2011). Two orthologs of the Drosophila E3 ligase dRing, Ring1a and Ring1b, are found in mammals and amphibians, whereas only a single gene that is most homologous to Ring1b has been identified in zebrafish (Le Faou et al, 2011;Vidal, 2009).…”

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

“…PRC2 catalyzes the methylation of H3K27; the methylation of H3K27, particularly trimethylation, is the main hallmark of PcG-mediated silencing (Levine et al, 2004;Ringrose et al, 2003), which occurs through enzymatic activity (in association with PRC1). In addition to the nonenzymatic chromatin-compacting regulatory effect of PRC1 (Eskeland et al, 2010), this Pc complex is able to ubiquitylate histone H2A through Ring1A and Ring1B (for reviews, see Eckert et al, 2011;Richly et al, 2011;Vidal, 2009).…”