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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和粘着蛋白在调节CFTR基因座的高阶结构和表达中具有独特的作用

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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：整个基因组中更高阶的染色质结构部分地由建筑蛋白CCCTC结合因子（CTCF）和粘着蛋白复合物维持，它们共同位于整个基因组的许多位点。在这里，我们检查这些蛋白质在介导的染色质结构在囊性纤维化跨膜电导调节剂（CFTR）基因中的作用。 CFTR包含将近200 kb，两侧是CTCF结合增强剂阻断绝缘子元件，并受细胞类型特异性内含子增强子调控，后者与活性基因座的启动子相连。 SiRNA介导的CTCF或粘着蛋白成分RAD21的耗竭表明，这两个因素在调节CFTR的较高阶组织中具有不同的作用。 CTCF介导CTCF /粘着蛋白结合位点之间的相互作用，其中一些具有增强剂阻断性绝缘子活性。粘着蛋白具有这种束缚作用，但是还稳定了启动子与顺式作用内含子元件（包括增强子）之间的相互作用，后者也取决于叉头盒A1 / A2（FOXA1 / A2）转录因子（TFs）。通过消耗CTCF或RAD21破坏CFTR基因的三维结构会增加基因表达，并伴随着组蛋白修饰的改变和TF在整个基因位点的占据，并导致基因从核外围被内在化。

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