CHD6 regulates the topological arrangement of the CFTR locus
CHD6 regulates the topological arrangement of the CFTR locus
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DOI：
10.1093/hmg/ddv032
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发表时间：
2015-05-15
影响因子：
3.5
通讯作者：
Walsh, Martin J.
中科院分区：
文献类型：
--
作者：
Sancho, Ana;Li, SiDe;Walsh, Martin J.
转录的控制是通过远端基因组调控元件之间协调良好的空间和时间相互作用来调节的，这些调控元件是专门的细胞类型和发育基因表达程序所需的。随着最近的研究结果，CFTR已经作为一个模型来理解管理远端染色体内接触的全基因组和拓扑组织的原则，因为它涉及到转录控制。这是由于DNA酶超敏位点的广泛表征、染色质的修饰、转录因子结合位点以及这些位点在CFTR中的排列与上皮细胞类型中的限制性表达一致。在这里，我们确定CHD 6从几个染色质重塑蛋白作为一个假定的CFTR表达的表观遗传调节剂之间的屏幕。此外，我们发现CTCF与CHD 6的相互作用与先前描述的CTCF在CFTR调节中的作用一致。我们的研究结果表明，CHD 6蛋白位于多个转录复合物的基础结构中，如FACT，PBAF，PAF 1C，Mediator，SMC/Cohesion和MLL复合物。该模型强调CHD 6通过将CFTR的顺式作用调控元件拴系在这些多亚基转录蛋白复合物附近而促进的基本作用。最后，我们指出CHD 6在结构上协调CFTR基因内元件之间的三维狭窄，CFTR基因内元件与几种细胞类型特异性转录因子如CDX 2、SOX 18、HNF 4 α和HNF 1 α结合。因此，我们的研究结果揭示了CFTR表达的表观遗传调控的新见解，而CFTR基因拓扑结构的操作可以被认为是治疗囊性纤维化和/或胰腺炎的特定适应症。
The control of transcription is regulated through the well-coordinated spatial and temporal interactions between distal genomic regulatory elements required for specialized cell-type and developmental gene expression programs. With recent findings CFTR has served as a model to understand the principles that govern genome-wide and topological organization of distal intra-chromosomal contacts as it relates to transcriptional control. This is due to the extensive characterization of the DNase hypersensitivity sites, modification of chromatin, transcription factor binding sites and the arrangement of these sites in CFTR consistent with the restrictive expression in epithelial cell types. Here, we identified CHD6 from a screen among several chromatin-remodeling proteins as a putative epigenetic modulator of CFTR expression. Moreover, our findings of CTCF interactions with CHD6 are consistent with the role described previously for CTCF in CFTR regulation. Our results now reveal that the CHD6 protein lies within the infrastructure of multiple transcriptional complexes, such as the FACT, PBAF, PAF1C, Mediator, SMC/Cohesion and MLL complexes. This model underlies the fundamental role CHD6 facilitates by tethering cis-acting regulatory elements of CFTR in proximity to these multi-subunit transcriptional protein complexes. Finally, we indicate that CHD6 structurally coordinates a three-dimensional stricture between intragenic elements of CFTR bound by several cell-type specific transcription factors, such as CDX2, SOX18, HNF4 alpha and HNF1 alpha. Therefore, our results reveal new insights into the epigenetic regulation of CFTR expression, whereas the manipulation of CFTR gene topology could be considered for treating specific indications of cystic fibrosis and/or pancreatitis.