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      CTCF as a multifunctional protein in genome regulation and gene expression

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          Abstract

          CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein and is best known as a transcription factor. It can function as a transcriptional activator, a repressor or an insulator protein, blocking the communication between enhancers and promoters. CTCF can also recruit other transcription factors while bound to chromatin domain boundaries. The three-dimensional organization of the eukaryotic genome dictates its function, and CTCF serves as one of the core architectural proteins that help establish this organization. The mapping of CTCF-binding sites in diverse species has revealed that the genome is covered with CTCF-binding sites. Here we briefly describe the diverse roles of CTCF that contribute to genome organization and gene expression.

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          A map of the cis-regulatory sequences in the mouse genome.

          The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.
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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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              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

                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group
                1226-3613
                2092-6413
                June 2015
                05 June 2015
                1 June 2015
                : 47
                : 6
                : e166
                Affiliations
                [1 ]Department of Biological Sciences, College of Natural Sciences, Seoul National University , Seoul, Korea
                Author notes
                [* ]Department of Biological Sciences, College of Natural Sciences, Seoul National University , Building 504, Room 202, 599 Gwanangno, Gwanak-gu, Seoul 151-747, Korea. E-mail: kaang@ 123456snu.ac.kr
                Article
                emm201533
                10.1038/emm.2015.33
                4491725
                26045254
                afdb4463-baba-4797-bc3c-a96a7ab34463
                Copyright © 2015 KSBMB.

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 19 December 2014
                : 08 February 2015
                : 27 February 2015
                Categories
                Review

                Molecular medicine
                Molecular medicine

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