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      Functional role of dimerization and CP190 interacting domains of CTCF protein in Drosophila melanogaster.

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          Abstract

          Insulators play a central role in gene regulation, chromosomal architecture and genome function in higher eukaryotes. To learn more about how insulators carry out their diverse functions, we have begun an analysis of the Drosophila CTCF (dCTCF). CTCF is one of the few insulator proteins known to be conserved from flies to man.

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          Cohesin mediates transcriptional insulation by CCCTC-binding factor.

          Kerstin Wendt, Keisuke Yoshida, Takehiko Itoh … (2008)
          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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            Cohesins functionally associate with CTCF on mammalian chromosome arms.

            Vania Parelho, Suzana Hadjur, Mikhail Spivakov … (2008)
            Cohesins mediate sister chromatid cohesion, which is essential for chromosome segregation and postreplicative DNA repair. In addition, cohesins appear to regulate gene expression and enhancer-promoter interactions. These noncanonical functions remained unexplained because knowledge of cohesin-binding sites and functional interactors in metazoans was lacking. We show that the distribution of cohesins on mammalian chromosome arms is not driven by transcriptional activity, in contrast to S. cerevisiae. Instead, mammalian cohesins occupy a subset of DNase I hypersensitive sites, many of which contain sequence motifs resembling the consensus for CTCF, a DNA-binding protein with enhancer blocking function and boundary-element activity. We find cohesins at most CTCF sites and show that CTCF is required for cohesin localization to these sites. Recruitment by CTCF suggests a rationale for noncanonical cohesin functions and, because CTCF binding is sensitive to DNA methylation, allows cohesin positioning to integrate DNA sequence and epigenetic state.
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              The protein CTCF is required for the enhancer blocking activity of vertebrate insulators.

              Adam Bell, Adam West, Gary Felsenfeld (1999)
              An insulator is a DNA sequence that can act as a barrier to the influences of neighboring cis-acting elements, preventing gene activation, for example, when located between an enhancer and a promoter. We have identified a 42 bp fragment of the chicken beta-globin insulator that is both necessary and sufficient for enhancer blocking activity in human cells. We show that this sequence is the binding site for CTCF, a previously identified eleven-zinc finger DNA-binding protein that is highly conserved in vertebrates. CTCF sites are present in all of the vertebrate enhancer-blocking elements we have examined. We suggest that directional enhancer blocking by CTCF is a conserved component of gene regulation in vertebrates.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): BMC Biol.
                Title: BMC biology
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 1741-7007
                ISSN (Print): 1741-7007
                Publication date (Electronic): Aug 07 2015
                Volume: 13
                Affiliations
                [1 ] Department of the Control of Genetic Processes, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
                [2 ] Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
                [3 ] Department of Biology, Nikolaev V.A. Sukhomlinsky National University, Nikolaev, Ukraine.
                [4 ] Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
                [5 ] Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia. pschedl@Princeton.EDU.
                [6 ] Department of Molecular Biology, Princeton University, Princeton, NJ, USA. pschedl@Princeton.EDU.
                [7 ] Department of the Control of Genetic Processes, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia. georgiev_p@mail.ru.
                Article
                Publisher Item ID: 10.1186/s12915-015-0168-7
                DOI: 10.1186/s12915-015-0168-7
                PMC ID: 4528719
                PubMed ID: 26248466
                SO-VID: e242838a-3058-4cfc-9b05-e0bbc1d3f838
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