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      Motif oriented high-resolution analysis of ChIP-seq data reveals the topological order of CTCF and cohesin proteins on DNA

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          Abstract

          Background

          ChIP-seq provides a wealth of information on the approximate location of DNA-binding proteins genome-wide. It is known that the targeted motifs in most cases can be found at the peak centers. A high resolution mapping of ChIP-seq peaks could in principle allow the fine mapping of the protein constituents within protein complexes, but the current ChIP-seq analysis pipelines do not target the basepair resolution strand specific mapping of peak summits.

          Results

          The approach proposed here is based on i) locating regions that are bound by a sufficient number of proteins constituting a complex; ii) determining the position of the underlying motif using either a direct or a de novo motif search approach; and iii) determining the exact location of the peak summits with respect to the binding motif in a strand specific manner. We applied this method for analyzing the CTCF/cohesin complex, which holds together DNA loops. The relative positions of the constituents of the complex were determined with one-basepair estimated accuracy. Mapping the positions on a 3D model of DNA made it possible to deduce the approximate local topology of the complex that allowed us to predict how the CTCF/cohesin complex locks the DNA loops. As the positioning of the proteins was not compatible with previous models of loop closure, we proposed a plausible “double embrace” model in which the DNA loop is held together by two adjacent cohesin rings in such a way that the ring anchored by CTCF to one DNA duplex encircles the other DNA double helix and vice versa.

          Conclusions

          A motif-centered, strand specific analysis of ChIP-seq data improves the accuracy of determining peak positions. If a genome contains a large number of binding sites for a given protein complex, such as transcription factor heterodimers or transcription factor/cofactor complexes, the relative position of the constituent proteins on the DNA can be established with an accuracy that allow one to deduce the local topology of the protein complex. The proposed high resolution mapping approach of ChIP-seq data is applicable for detecting the contact topology of DNA-binding protein complexes.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12864-016-2940-7) contains supplementary material, which is available to authorized users.

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          Most cited references28

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          Database resources of the National Center for Biotechnology Information

          In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides analysis and retrieval resources for the data in GenBank and other biological data available through NCBI's web site. NCBI resources include Entrez, the Entrez Programming Utilities, My NCBI, PubMed, PubMed Central, Entrez Gene, the NCBI Taxonomy Browser, BLAST, BLAST Link, Electronic PCR, OrfFinder, Spidey, Splign, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, Cancer Chromosomes, Entrez Genome, Genome Project and related tools, the Trace, Assembly, and Short Read Archives, the Map Viewer, Model Maker, Evidence Viewer, Clusters of Orthologous Groups, Influenza Viral Resources, HIV-1/Human Protein Interaction Database, Gene Expression Omnibus, Entrez Probe, GENSAT, Database of Genotype and Phenotype, Online Mendelian Inheritance in Man, Online Mendelian Inheritance in Animals, the Molecular Modeling Database, the Conserved Domain Database, the Conserved Domain Architecture Retrieval Tool and the PubChem suite of small molecule databases. Augmenting the web applications are custom implementations of the BLAST program optimized to search specialized data sets. These resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov.
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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: its roles and mechanisms.

              The cohesin complex is a major constituent of interphase and mitotic chromosomes. Apart from its role in mediating sister chromatid cohesion, it is also important for DNA double-strand-break repair and transcriptional control. The functions of cohesin are regulated by phosphorylation, acetylation, ATP hydrolysis, and site-specific proteolysis. Recent evidence suggests that cohesin acts as a novel topological device that traps chromosomal DNA within a large tripartite ring formed by its core subunits.
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                Author and article information

                Contributors
                nagygergely@med.unideb.hu
                czipa.erik@med.unideb.hu
                steiner.laszlo@ud-genomed.hu
                black007@abc.hu
                pongor@itk.ppke.hu
                nagyl@med.unideb.hu
                barta.endre@unideb.hu
                Journal
                BMC Genomics
                BMC Genomics
                BMC Genomics
                BioMed Central (London )
                1471-2164
                15 August 2016
                15 August 2016
                2016
                : 17
                : 637
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4032 Hungary
                [2 ]UD-GenoMed Medical Genomic Technologies Research & Development Services Ltd., Nagyerdei krt. 98., Debrecen, H-4032 Hungary
                [3 ]Agricultural Genomics and Bioinformatics Group, Agricultural Biotechnology Institute, NARIC, Gödöllő, H-2100 Hungary
                [4 ]Faculty of Information Technology and Bionics, Pázmány Péter Catholic University Budapest H-1083, Gödöllő, Hungary
                [5 ]MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen, H-4032 Hungary
                [6 ]Present address: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK
                Author information
                http://orcid.org/0000-0002-6753-0714
                Article
                2940
                10.1186/s12864-016-2940-7
                4986361
                27526722
                767dd596-1275-4c64-bd71-4b70d5e99e69
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 April 2016
                : 14 July 2016
                Funding
                Funded by: Hungarian Ministry of Agriculture
                Award ID: NAIK-MBK/M71411
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005909, Nemzeti Fejlesztési Minisztérium;
                Award ID: TÁMOP-4.2.2.C-11/1/KONV-2012-0010
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Genetics
                ctcf,cohesin,chip-seq,dna loop
                Genetics
                ctcf, cohesin, chip-seq, dna loop

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