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首页> 外文期刊>Nucleic Acids Research >Architectural proteins CTCF and cohesin have distinct roles in modulating the higher order structure and expression of the CFTR locus
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Architectural proteins CTCF and cohesin have distinct roles in modulating the higher order structure and expression of the CFTR locus

机译：建筑蛋白CTCF和Cohesin在调制更高阶结构和CFTR基因座的表达方面具有明显的作用

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摘要

Higher order chromatin structures across the genome are maintained in part by the architectural proteins CCCTC binding factor (CTCF) and the cohesin complex, which co-localize at many sites across the genome. Here, we examine the role of these proteins in mediating chromatin structure at the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encompasses nearly 200 kb flanked by CTCF-binding enhancer-blocking insulator elements and is regulated by cell-type-specific intronic enhancers, which loop to the promoter in the active locus. SiRNA-mediated depletion of CTCF or the cohesin component, RAD21, showed that these two factors have distinct roles in regulating the higher order organization of CFTR. CTCF mediates the interactions between CTCF/cohesin binding sites, some of which have enhancer-blocking insulator activity. Cohesin shares this tethering role, but in addition stabilizes interactions between the promoter and cis-acting intronic elements including enhancers, which are also dependent on the forkhead box A1/A2 (FOXA1/A2) transcription factors (TFs). Disruption of the three-dimensional structure of the CFTR gene by depletion of CTCF or RAD21 increases gene expression, which is accompanied by alterations in histone modifications and TF occupancy across the locus, and causes internalization of the gene from the nuclear periphery.
机译：整个基因组的高阶染色质结构部分由建筑蛋白质CCCTC结合因子（CTCF）和CTCF复合物组成，其在基因组上的许多位点共定出。在这里，我们研究这些蛋白质在染色纤维化跨膜电导调节剂（CFTR）基因中的染色质结构中的作用。 CFTR包括CTCF结合增强剂阻断绝缘体元件的近200kb，并且由细胞型特异性内肠增强剂调节，其在活性基因座中环绕着启动子。 SiRNA介导的CTCF或CONENIN组分RAD21的耗尽表明，这两个因素在调节CFTR的高阶组织方面具有明显的作用。 CTCF介导CTCF /休谷蛋白结合位点之间的相互作用，其中一些具有增强剂阻断绝缘体活性。 Cohesin共享这种束缚作用，但另外还稳定启动子和CIS作用肾内注册元件之间的相互作用，包括增强剂，也依赖于叉头盒A1 / A2（FOXA1 / A2）转录因子（TFS）。 CTCF或Rad21耗尽的CFTR基因的三维结构的破坏增加了基因表达，其伴随着在轨迹上的组蛋白修饰和TF占状的改变，并导致基因的内化来自核外围。

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  • 来源
    《Nucleic Acids Research》 |2014年第15期|共11页
  • 作者

    Gosalia Nehal; Neems Daniel; Kerschner Jenny L.; Kosak Steven T.; Harris Ann;

  • 作者单位

    Northwestern Univ Lurie Childrens Res Ctr Feinberg Sch Med Human Mol Genet Program Chicago IL 60611 USA;

    Northwestern Univ Dept Cell &

    amp;

    Mol Biol Feinberg Sch Med Chicago IL 60611 USA;

    Northwestern Univ Lurie Childrens Res Ctr Feinberg Sch Med Human Mol Genet Program Chicago IL 60611 USA;

    Northwestern Univ Dept Cell &

    amp;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
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