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      The Chromatin Remodelling Enzymes SNF2H and SNF2L Position Nucleosomes adjacent to CTCF and Other Transcription Factors

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Within the genomes of metazoans, nucleosomes are highly organised adjacent to the binding sites for a subset of transcription factors. Here we have sought to investigate which chromatin remodelling enzymes are responsible for this. We find that the ATP-dependent chromatin remodelling enzyme SNF2H plays a major role organising arrays of nucleosomes adjacent to the binding sites for the architectural transcription factor CTCF sites and acts to promote CTCF binding. At many other factor binding sites SNF2H and the related enzyme SNF2L contribute to nucleosome organisation. The action of SNF2H at CTCF sites is functionally important as depletion of CTCF or SNF2H affects transcription of a common group of genes. This suggests that chromatin remodelling ATPase’s most closely related to the Drosophila ISWI protein contribute to the function of many human gene regulatory elements.

          Author Summary

          CTCF is a transcriptional regulator acting as an insulator element interfering with enhancer function and as a boundary between chromatin domains. CTCF has been shown to organise an exquisite array of phased nucleosomes flanking its binding sites. Here we identified SNF2H as the enzyme primarily responsible for organising the extended arrays of nucleosomes adjacent to CTCF sites. We find that SNF2H acts to maintain the occupancy of CTCF at its binding sites, but does not act as a general loading factor for CTCF’s binding partner cohesin. SNF2H’s action at CTCF sites is functionally important as overlapping cohorts of genes are affected by depletion of CTCF or SNF2H. Other transcription factors also organise nucleosomes and we find that the SNF2H and the related enzyme SNF2L contribute to organising nucleosomes at many of these sites.

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          Most cited references 46

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          Genome-scale identification of nucleosome positions in S. cerevisiae.

          The positioning of nucleosomes along chromatin has been implicated in the regulation of gene expression in eukaryotic cells, because packaging DNA into nucleosomes affects sequence accessibility. We developed a tiled microarray approach to identify at high resolution the translational positions of 2278 nucleosomes over 482 kilobases of Saccharomyces cerevisiae DNA, including almost all of chromosome III and 223 additional regulatory regions. The majority of the nucleosomes identified were well-positioned. We found a stereotyped chromatin organization at Pol II promoters consisting of a nucleosome-free region approximately 200 base pairs upstream of the start codon flanked on both sides by positioned nucleosomes. The nucleosome-free sequences were evolutionarily conserved and were enriched in poly-deoxyadenosine or poly-deoxythymidine sequences. Most occupied transcription factor binding motifs were devoid of nucleosomes, strongly suggesting that nucleosome positioning is a global determinant of transcription factor access.
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            Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome.

            Insulator elements affect gene expression by preventing the spread of heterochromatin and restricting transcriptional enhancers from activation of unrelated promoters. In vertebrates, insulator's function requires association with the CCCTC-binding factor (CTCF), a protein that recognizes long and diverse nucleotide sequences. While insulators are critical in gene regulation, only a few have been reported. Here, we describe 13,804 CTCF-binding sites in potential insulators of the human genome, discovered experimentally in primary human fibroblasts. Most of these sequences are located far from the transcriptional start sites, with their distribution strongly correlated with genes. The majority of them fit to a consensus motif highly conserved and suitable for predicting possible insulators driven by CTCF in other vertebrate genomes. In addition, CTCF localization is largely invariant across different cell types. Our results provide a resource for investigating insulator function and possible other general and evolutionarily conserved activities of CTCF sites.
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              Cohesin mediates transcriptional insulation by CCCTC-binding factor.

              Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19/IGF2 (insulin-like growth factor 2) locus. This role of cohesin seems to be independent of its role in cohesion. We propose that cohesin functions as a transcriptional insulator, and speculate that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                28 March 2016
                March 2016
                : 12
                : 3
                Affiliations
                [1 ]Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom
                [2 ]Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, United Kingdom
                Babraham Institute, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NW VS TG PS SR TOH. Performed the experiments: NW VS. Analyzed the data: NW VS TG PS TOH. Contributed reagents/materials/analysis tools: NW VS SR. Wrote the paper: NW VS SR TOH.

                Article
                PGENETICS-D-15-01986
                10.1371/journal.pgen.1005940
                4809547
                27019336
                © 2016 Wiechens et al

                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.

                Page count
                Figures: 7, Tables: 1, Pages: 25
                Product
                Funding
                This work was supported by Wellcome Trust grant 095062 ( http://www.wellcome.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromatin
                Nucleosomes
                Biology and Life Sciences
                Genetics
                Epigenetics
                Chromatin
                Nucleosomes
                Biology and Life Sciences
                Genetics
                Gene Expression
                Chromatin
                Nucleosomes
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Transcription Factors
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcription Factors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Regulatory Proteins
                Transcription Factors
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromatin
                Biology and Life Sciences
                Genetics
                Epigenetics
                Chromatin
                Biology and Life Sciences
                Genetics
                Gene Expression
                Chromatin
                Biology and life sciences
                Genetics
                Gene expression
                Gene regulation
                Small interfering RNAs
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                Small interfering RNAs
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Gene Mapping
                Nucleosome Mapping
                Research and Analysis Methods
                Molecular Biology Techniques
                Gene Mapping
                Nucleosome Mapping
                Biology and Life Sciences
                Genetics
                Genetic Interference
                Biology and Life Sciences
                Genetics
                Gene Expression
                Custom metadata
                Sequence data is accessible at the European nucleotide archive (ENA) http://www.ebi.ac.uk/ena/about/data-repositories under accession number PRJEB8713.

                Genetics

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