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      The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis

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          Abstract

          Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.

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          Most cited references80

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          Mechanisms of polycomb gene silencing: knowns and unknowns.

          Polycomb proteins form chromatin-modifying complexes that implement transcriptional silencing in higher eukaryotes. Hundreds of genes are silenced by Polycomb proteins, including dozens of genes that encode crucial developmental regulators in organisms ranging from plants to humans. Two main families of complexes, called Polycomb repressive complex 1 (PRC1) and PRC2, are targeted to repressed regions. Recent studies have advanced our understanding of these complexes, including their potential mechanisms of gene silencing, the roles of chromatin modifications, their means of delivery to target genes and the functional distinctions among variant complexes. Emerging concepts include the existence of a Polycomb barrier to transcription elongation and the involvement of non-coding RNAs in the targeting of Polycomb complexes. These findings have an impact on the epigenetic programming of gene expression in many biological systems.
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            Genome-wide analysis of estrogen receptor binding sites.

            The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer.
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              The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.

              The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                6 March 2013
                : 8
                : 3
                : e58083
                Affiliations
                [1 ]Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
                [2 ]Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
                [3 ]Department of Bioinformatics – BiGCaT, Maastricht University Medical Centre, Maastricht, The Netherlands
                North Carolina State University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: F. Spaapen GGHvdA LME JWV. Performed the experiments: F. Spaapen GGHvdA MMJC PP CR VEHD DAMS YP F. Schweitzer TW LE JWV. Analyzed the data: F. Spaapen GGHvdA MMJC PP CR VEHD DAMS YP F. Schweitzer TW LE JWV. Wrote the paper: F. Spaapen GGHvdA JWV.

                Article
                PONE-D-12-22721
                10.1371/journal.pone.0058083
                3590300
                23483971
                66b2c7a0-5a0e-425b-9b44-ab7718a6ac0c
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 July 2012
                : 30 January 2013
                Page count
                Pages: 16
                Funding
                This work was supported by European Molecular Biology Organization (Germany) ASTF5-2009 (FS) and the René Vogels foundation (FS); Dutch Scientific Organization (ZonMW-NWO): VIDI grant 016.046.362 (JWV); tUL Grant (JWV). LLP14 Grant Netherlands Reuma foundation (JWV, LWvR) and a transnational University of Limburg grant (JWV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Cell Differentiation
                Molecular Development
                Molecular Cell Biology
                Gene Expression
                DNA transcription
                Histone Modification
                Chromatin
                RNA interference
                Signal Transduction
                Signaling in Cellular Processes
                Mitogenic Signaling
                Signaling Pathways

                Uncategorized
                Uncategorized

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