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      FBXL19 recruits CDK-Mediator to CpG islands of developmental genes priming them for activation during lineage commitment

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          Abstract

          CpG islands are gene regulatory elements associated with the majority of mammalian promoters, yet how they regulate gene expression remains poorly understood. Here, we identify FBXL19 as a CpG island-binding protein in mouse embryonic stem (ES) cells and show that it associates with the CDK-Mediator complex. We discover that FBXL19 recruits CDK-Mediator to CpG island-associated promoters of non-transcribed developmental genes to prime these genes for activation during cell lineage commitment. We further show that recognition of CpG islands by FBXL19 is essential for mouse development. Together this reveals a new CpG island-centric mechanism for CDK-Mediator recruitment to developmental gene promoters in ES cells and a requirement for CDK-Mediator in priming these developmental genes for activation during cell lineage commitment.

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          Transcription factors: from enhancer binding to developmental control.

          François Spitz, Eileen E M Furlong (2012)
          Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.
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            The Mediator complex: a central integrator of transcription.

            Benjamin Allen, Dylan J. Taatjes (2015)
            The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator - a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.
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              CpG islands--'a rough guide'.

              Robert S. Illingworth, Adrian P. Bird (2009)
              Mammalian genomes are punctuated by DNA sequences containing an atypically high frequency of CpG sites termed CpG islands (CGIs). CGIs generally lack DNA methylation and associate with the majority of annotated gene promoters. Many studies, however, have identified examples of CGI methylation in malignant cells, leading to improper gene silencing. CGI methylation also occurs in normal tissues and is known to function in X-inactivation and genomic imprinting. More recently, differential methylation has been shown between tissues, suggesting a potential role in transcriptional regulation during cell specification. Many of these tissue-specific methylated CGIs localise to regions distal to promoters, the regulatory function of which remains to be determined.
              Article 0 comments Cited 280 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Angelika Feldmann
                Haruhiko Koseki:
                ORCID: http://orcid.org/0000-0001-8424-5854
                Robert J Klose:
                ORCID: http://orcid.org/0000-0002-8726-7888
                Joaquín M Espinosa: Role: Reviewing Editor
                Journal
                Journal ID (nlm-ta): eLife
                Journal ID (iso-abbrev): Elife
                Journal ID (publisher-id): eLife
                Title: eLife
                Publisher: eLife Sciences Publications, Ltd
                ISSN (Electronic): 2050-084X
                Publication date (Electronic, pub): 29 May 2018
                Publication date Collection: 2018
                Volume: 7
                Electronic Location Identifier: e37084
                Affiliations
                [1 ]deptDepartment of Biochemistry University of Oxford OxfordUnited Kingdom
                [2 ]deptLaboratory for Developmental Genetics RIKEN Center for Integrative Medical Sciences YokohamaJapan
                [3 ]deptDepartment of Technology Development Kazusa DNA Research Institute KisarazuJapan
                [4 ]deptNuffield Department of Medicine TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford OxfordUnited Kingdom
                [5 ]deptCREST Japan Science and Technology Agency KawaguchiJapan
                [6]University of Colorado School of Medicine United States
                [7]University of Colorado School of Medicine United States
                Author notes
                [‡]

                Agilent Technologies, Waldbronn, Germany.

                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-5669-1240
                http://orcid.org/0000-0001-8424-5854
                http://orcid.org/0000-0002-8726-7888
                Article
                Publisher ID: 37084
                DOI: 10.7554/eLife.37084
                PMC ID: 5997449
                PubMed ID: 29809150
                SO-VID: 1af055d0-1d42-4edb-978f-35a5421b9eeb
                Copyright © © 2018, Dimitrova et al
                License:

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 29 March 2018
                Date accepted : 26 May 2018
                Funding
                Funded by: Sir Henry Wellcome Postdoctoral Fellowship;
                Award ID: 110286/Z/15/Z
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome;
                Award ID: 098024/Z/11/Z
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 681440
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001255, Lister Institute of Preventive Medicine;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Subject: Research Article
                Subject: Chromosomes and Gene Expression
                Subject: Developmental Biology and Stem Cells
                Custom metadata
                Author impact statement The ZF-CxxC protein FBXL19 recruits kinase-associated Mediator to CpG islands of silent developmental genes in embryonic stem cells, which primes these genes for activation during differentiation and is required for embryonic development.

                ScienceOpen disciplines: Life sciences
                Keywords: chromatin,cpg islands,cdk-mediator,zf-cxxc,transcription,lineage commitment,mouse
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: chromatin, cpg islands, cdk-mediator, zf-cxxc, transcription, lineage commitment, mouse

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