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Cover Petra B UvA-DARE (Digital Academic Repository) The role of Polycomb group proteins throughout development : f(l)avoring repression van der Stoop, P.M. Link to publication Citation for published version (APA): van der Stoop, P. M. (2009). The role of Polycomb group proteins throughout development : f(l)avoring repression. Amsterdam: Nederlands Kanker Instituut - Antoni Van Leeuwenhoekziekenhuis. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) Download date: 27 Oct 2019 Chapter 4 Ubiquitin E3 Ligase Ring1b/Rnf2 of Polycomb Repressive Complex 1 Contributes to Stable Maintenance of Mouse Embryonic Stem Cells Petra van der Stoop*, Erwin A. Boutsma*, Danielle Hulsman, Sonja Noback, Mike Heimerikx, Ron M. Kerkhoven, J. Willem Voncken, Lodewyk F.A. Wessels, Maarten van Lohuizen * These authors contributed equally to this work Adapted from: PLoS ONE (2008) 3(5): e2235 Ring1b regulates ES cell fate Ubiquitin E3 Ligase Ring1b/Rnf2 of Polycomb Repressive Complex 1 Contributes to Stable Maintenance of Mouse Embryonic Stem Cells Petra van der Stoop1*, Erwin A. Boutsma.1*, Danielle Hulsman1, Sonja Noback1, Mike Heimerikx2, Ron M. Kerkhoven2, J. Willem Voncken4, Lodewyk F.A. Wessels3, Maarten van Lohuizen1,5# 1Division of Molecular Genetics, and 2Center for Biomedical Genetics, and 3Bioinformatics and Statistics, Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands, 4Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands, 5Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. * These authors contributed equally to this work Background Polycomb repressive complex 1 (PRC1) core member Ring1b/Rnf2, with ubiquitin E3 ligase activity towards histone H2A at lysine 119, is essential for early embryogenesis. To obtain more insight into the role of Ring1b in early development, we studied its function in mouse embryonic stem (ES) cells. Methodology/Principle Findings We investigated the effects of Ring1b ablation on transcriptional regulation using Ring1b conditional knockout ES cells and large-scale gene expression analysis. The absence of Ring1b results in aberrant expression of key developmental genes and deregulation of specific differentiation-related pathways, including TGFbeta signaling, cell cycle regulation and cellular communication. Moreover, ES cell markers, including Zfp42/Rex-1 and Sox2, are downregulated. Importantly, retained expression of ES cell regulators Oct4, Nanog and alkaline phosphatase indicates that Ring1b-deficient ES cells retain important ES cell specific characteristics. Comparative analysis of our expression profiling data with previously published global binding studies shows that the genes that are bound by Ring1b in ES cells have bivalent histone marks, i.e. both active H3K4me3 and repressive H3K27me3, or the active H3K4me3 histone mark alone and are associated with CpG-‘rich’ promoters. However, deletion of Ring1b results in deregulation, mainly derepression, of only a subset of these genes, suggesting that additional silencing mechanisms are involved in repression of the other Ring1b bound genes in ES cells. Conclusions Ring1b is essential to stably maintain an undifferentiated state of mouse ES cells by repressing genes with important roles during differentiation and development. These genes are characterized by high CpG content promoters and bivalent histone marks or the active H3K4me3 histone mark alone. 69 Chapter 4 Introduction 2000; Takihara et al, 1997; van der Lugt et al, 1994; Voncken et al, 2003). PcG proteins PcG proteins have initially been identified were shown to be important for self-renewal in Drosophila as transcriptional repressors and maintaining pluripotency of ES cells required for correct expression of homeotic (Boyer et al, 2006; Pasini et al, 2007; Valk- (Hox) genes. By means of chromatin Lingbeek et al, 2004). ES cells are derived remodeling, PcG proteins maintain stable from the inner cell mass of pre-implantation gene repression to ensure proper embryonic blastocysts (Evans and Kaufman, 1981). ES development. In mammals, two biochemically can self-renew and maintain a pluripotent, and functionally distinct PcG core complexes undifferentiated state under the right have been identified (Lund and van conditions in vitro, while retaining the Lohuizen, 2004). Mammalian polycomb capacity to differentiate into every cell type repressive complex 1 (PRC1) consists of required during development in vitro and close homologs of the Drosophila PRC1 in vivo when reintroduced back into a host core members Ph, Pc, Psc and dRing (Lund blastocyst (Beddington and Robertson, and van Lohuizen, 2004; Ringrose and Paro, 1989). Genome-wide and candidate-based 2004). Ring1b/Rnf2, the mouse homolog of studies revealed that PcG proteins maintain dRing, acts as a ubiquitin E3 ligase towards this undifferentiated state of ES cells through histone H2A at lysine 119 resulting in mono- direct repression of developmental genes ubiquitinated H2A (uH2A) (Buchwald et (Boyer et al, 2006; Bracken et al, 2006; Lee al, 2006; Wang et al, 2004). Ezh2/Kmt6, a et al, 2006; Squazzo et al, 2006; Tolhuis et methyltransferase that trimethylates histone al, 2006). Developmental genes are largely H3 at lysine 27 (H3K27me3), acts in complex associated with bivalent (i.e. both repressive with Suz12 and Eed, constituting Polycomb H3K27me3 and active H3K4me3) histone repressive complex 2 (PRC2) (Cao et al, marks and are silent or expressed at very 2002; Kirmizis et al, 2004; Kuzmichev et al, low levels in ES cells (Azuara et al, 2006; 2002). PRC1 and PCR2 do not physically Bernstein et al, 2006; Mikkelsen et al, 2007). interact, but the Ezh2 catalyzed histone mark Bivalent domains tend to resolve during H3K27me3 is recognized by PRC1 member development (Azuara et al, 2006; Bernstein Pc, providing a mechanism of communication et al, 2006; Mikkelsen et al, 2007). Therefore, between the two complexes (Fischle et it is suggested that this bivalent chromatin al, 2003). Furthermore, PRC1 binding to state poises genes for transcriptional chromatin requires PRC2, although PRC2- activation (loss of H3K27me3) or prolonged independent recruitment of PRC1 is also repression (loss of H3K4me3 or both marks) reported (Hernandez-Munoz et al, 2005b; during later developmental stages. Only Schoeftner et al, 2006). The counteracting recently, it was shown that Ring1b-mediated trithorax group (TrxG) proteins mediate an uH2A deposition at repressed bivalent active transcriptional state by methylation of genes restrains a poised RNA polymerase histone H3 at lysine 4 (H3K4me3) (Ringrose II (RNAPII) configuration (Stock et al, and Paro, 2004). 2007). Conditional deletion of Ring1b and Proper expression of PRC2 proteins subsequent loss of uH2A from the promoter is essential during early embryonic and coding region resulted in release of development, since mice lacking one of poised RNAPII and gene derepression. More these proteins die due to gastrulation evidence for a direct role of uH2A in negative defects (Faust et al, 1995; O’Carroll et al, transcriptional regulation was found by 2001; Pasini et al, 2004). In contrast, PRC1 another group, which investigated the role of members appear to be more important during histone H2A E3 ligase 2A-HUB in repressing later stages of development, with the clear chemokine genes in human monocytes exception of Ring1b, which evokes an early (Zhou et al, 2008). They showed that the embryonic lethal phenotype similar to PRC2 presence of uH2A in the promoter-proximal null mice (Akasaka et al, 1996; del Mar et al, region physically blocks the recruitment of 70 Ring1b regulates ES cell fate FACT, thereby causing RNAPII-dependent locus of Ring1b-/Lox ES cells, hereafter transcription elongation to pause. named Ring1b-/Lox;CreERT2 ES cells. The To explore the role of Ring1b in regulation of presence of loxP sequences in the genomic gene expression during early development, locus of Ring1b did not alter the expression we analyzed genome-wide changes in of Ring1b in ES cells. Accordingly, Ring1b-/ gene transcription following deletion of Lox and Ring1b-/Lox;CreERT2 mice developed Ring1b in ES cells. Hereto, we employed an indistinguishable from wild type mice (E.B, inducible knockout system and performed M.v.L, unpublished results). a genome-wide screen using microarrays Addition of 4-OHT to the culture medium to identify genes governed by Ring1b. We resulted in recombination of the Ring1b identify several processes and pathways conditional allele in Ring1b-/Lox;CreERT2 ES differentially regulated in Ring1b-deficient ES cells and subsequent depletion of Ring1b
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