Chromatin remodeling mediated by the FOXA1/A2 transcription factors activates CFTR expression in intestinal epithelial cells
Chromatin remodeling mediated by the FOXA1/A2 transcription factors activates CFTR expression in intestinal epithelial cells
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DOI：
10.4161/epi.27696
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发表时间：
2014-04-01
期刊：
影响因子：
3.7
通讯作者：
Harris, Ann
中科院分区：
文献类型：
--
作者：
Kerschner, Jenny L.;Gosalia, Nehal;Harris, Ann
叉头框A转录因子FOXA 1和FOXA 2作为先锋因子发挥功能，打开凝聚的染色质并促进其他蛋白质的结合。我们先前表明，这些因子是转录网络的关键组成部分，该转录网络驱动肠上皮细胞中囊性纤维化跨膜传导调节因子（CFTR）位点的增强子功能。CFTR启动子明显缺乏组织特异性调控元件，并且基因的表达由多个顺式作用元件控制，所述顺式作用元件协调不同细胞类型中的基因表达。在这里，我们表明，同时耗尽FOXA 1和FOXA 2抑制CFTR的表达，并通过减少启动子和内含子顺式作用元件之间的相互作用改变了活性位点的三维结构。FOXA 1/A2的减少还改变了CFTR基因座上活性增强子标记H3 K27 ac和H3 K4 me 2的富集特征，并改变了单个顺式元件处的染色质可及性。此外，FOXA 1/A2的缺失抑制了转录网络的其他成员（包括HNF 1和CDX 2）向多个顺式元件的募集。这些数据揭示了FOXA 1/A2在肠上皮细胞中实现高水平CFTR表达的作用的复杂分子机制。
The forkhead box A transcription factors, FOXA1 and FOXA2, function as pioneer factors to open condensed chromatin and facilitate binding of other proteins. We showed previously that these factors are key components of a transcriptional network that drives enhancer function at the cystic fibrosis transmembrane conductance regulator (CFTR) locus in intestinal epithelial cells. The CFTR promoter apparently lacks tissue-specific regulatory elements and expression of the gene is controlled by multiple cis-acting elements, which coordinate gene expression in different cell types. Here we show that concurrent depletion of FOXA1 and FOXA2 represses CFTR expression and alters the three-dimensional architecture of the active locus by diminishing interactions between the promoter and intronic cis-acting elements. Reduction of FOXA1/A2 also modifies the enrichment profile of the active enhancer marks H3K27ac and H3K4me2 across the CFTR locus and alters chromatin accessibility at individual cis-elements. Moreover, loss of FOXA1/A2 suppresses the recruitment of other members of the transcriptional network including HNF1 and CDX2, to multiple cis-elements. These data reveal a complex molecular mechanism underlying the role of FOXA1/A2 in achieving high levels of CFTR expression in intestinal epithelial cells.