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      CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation.

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          Abstract

          Polycomb and Trithorax group proteins encode the epigenetic memory of cellular positional identity by establishing inheritable domains of repressive and active chromatin within the Hox clusters. Here we demonstrate that the CCCTC-binding factor (CTCF) functions to insulate these adjacent yet antagonistic chromatin domains during embryonic stem cell differentiation into cervical motor neurons. Deletion of CTCF binding sites within the Hox clusters results in the expansion of active chromatin into the repressive domain. CTCF functions as an insulator by organizing Hox clusters into spatially disjoint domains. Ablation of CTCF binding disrupts topological boundaries such that caudal Hox genes leave the repressed domain and become subject to transcriptional activation. Hence, CTCF is required to insulate facultative heterochromatin from impinging euchromatin to produce discrete positional identities.

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          Most cited references20

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          A gene complex controlling segmentation in Drosophila.

          E B Lewis (1978)
          The bithorax gene complex in Drosophila contains a minimum of eight genes that seem to code for substances controlling levels of thoracic and abdominal development. The state of repression of at least four of these genes is controlled by cis-regulatory elements and a separate locus (Polycomb) seems to code for a repressor of the complex. The wild-type and mutant segmentation patterns are consistent with an antero-posterior gradient in repressor concentration along the embryo and a proximo-distal gradient along the chromosome in the affinities for repressor of each gene's cis-regulatory element.
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            Molecular signals of epigenetic states.

            Epigenetic signals are responsible for the establishment, maintenance, and reversal of metastable transcriptional states that are fundamental for the cell's ability to "remember" past events, such as changes in the external environment or developmental cues. Complex epigenetic states are orchestrated by several converging and reinforcing signals, including transcription factors, noncoding RNAs, DNA methylation, and histone modifications. Although all of these pathways modulate transcription from chromatin in vivo, the mechanisms by which epigenetic information is transmitted through cell division remain unclear. Because epigenetic states are metastable and change in response to the appropriate signals, a deeper understanding of their molecular framework will allow us to tackle the dysregulation of epigenetics in disease.
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              Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains.

              Insulators are DNA elements that prevent inappropriate interactions between the neighboring regions of the genome. They can be functionally classified as either enhancer blockers or domain barriers. CTCF (CCCTC-binding factor) is the only known major insulator-binding protein in the vertebrates and has been shown to bind many enhancer-blocking elements. However, it is not clear whether it plays a role in chromatin domain barriers between active and repressive domains. Here, we used ChIP-seq to map the genome-wide binding sites of CTCF in three cell types and identified significant binding of CTCF to the boundaries of repressive chromatin domains marked by H3K27me3. Although we find an extensive overlapping of CTCF-binding sites across the three cell types, its association with the domain boundaries is cell-type-specific. We further show that the nucleosomes flanking CTCF-binding sites are well positioned. Interestingly, we found a complementary pattern between the repressive H3K27me3 and the active H2AK5ac regions, which are separated by CTCF. Our data indicate that CTCF may play important roles in the barrier activity of insulators, and this study provides a resource for further investigation of the CTCF function in organizing chromatin in the human genome.
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                Author and article information

                Journal
                Science
                Science (New York, N.Y.)
                1095-9203
                0036-8075
                Feb 27 2015
                : 347
                : 6225
                Affiliations
                [1 ] Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
                [2 ] Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
                [3 ] Department of Biology, New York University, New York, NY 10003, USA.
                [4 ] Department of Biology, New York University, New York, NY 10003, USA. danny.reinberg@nyumc.org eom204@nyu.edu.
                [5 ] Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. danny.reinberg@nyumc.org eom204@nyu.edu.
                Article
                347/6225/1017 NIHMS681260
                10.1126/science.1262088
                25722416
                963933fe-b01c-446c-a275-de1d42b85d53
                Copyright © 2015, American Association for the Advancement of Science.
                History

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