Krüppel-Like Factor 5 Regulates CFTR Expression Through Repression by Maintaining Chromatin Architecture Coupled with Direct Enhancer Activation.
Krüppel-Like Factor 5 Regulates CFTR Expression Through Repression by Maintaining Chromatin Architecture Coupled with Direct Enhancer Activation.
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DOI：
10.1016/j.jmb.2022.167561
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发表时间：
2022-05-30
影响因子：
5.6
通讯作者：
Harris, Ann
中科院分区：
文献类型：
--
作者：
Paranjapye, Alekh;NandyMazumdar, Monali;Harris, Ann
关键词：
单细胞rna测序已经准确鉴定了人类气道内表达囊性纤维化跨膜传导调节（CFTR）基因的细胞类型。低丰度的CFTR转录本在许多分泌细胞中可见，而高丰度的CFTR转录本仅限于罕见的肺离子细胞。在这里，我们关注的是在分泌室中协调基础CFTR表达的机制。CFTR的细胞选择性调控是通过募集顺式调控元件（CREs）在其不变的拓扑关联域中实现的。CRE活性由细胞类型选择性转录因子协调。其中一个因子kr<s:1> ppel样因子5 （KLF5）在人原代气道上皮细胞和气道细胞系中深刻抑制CFTR转录物和蛋白。本文揭示了KLF5对CFTR基因的作用机制。我们发现，从气道上皮细胞中去除或消融KLF5会改变CFTR位点的高阶染色质结构。正常基因表达所需的关键环相互作用被改变，H3K27ac活性染色质标记被重新分配，CTCF占用被改变。然而，关键气道细胞CRE中单个KLF5结合位点的突变可消除CFTR的表达。因此，KLF5具有直接激活和间接抑制作用，共同协调CFTR在气道中的表达。
Single cell RNA-sequencing has accurately identified cell types within the human airway that express the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) gene. Low abundance CFTR transcripts are seen in many secretory cells, while high levels are restricted to rare pulmonary ionocytes. Here we focus on the mechanisms coordinating basal CFTR expression in the secretory compartment. Cell-selective regulation of CFTR is achieved within its invariant topologically associating domain by the recruitment of cis-regulatory elements (CREs). CRE activity is coordinated by cell-type-selective transcription factors. One such factor, Krüppel-Like Factor 5 (KLF5), profoundly represses CFTR transcript and protein in primary human airway epithelial cells and airway cell lines. Here we reveal the mechanism of action of KLF5 upon the CFTR gene. We find that depletion or ablation of KLF5 from airway epithelial cells changes higher order chromatin structure at the CFTR locus. Critical looping interactions that are required for normal gene expression are altered, the H3K27ac active chromatin mark is redistributed, and CTCF occupancy is modified. However, mutation of a single KLF5 binding site within a pivotal airway cell CRE abolishes CFTR expression. Hence, KLF5 has both direct activating and indirect repressive effects, which together coordinate CFTR expression in the airway.
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影响因子：
16.6
作者：
Corvol H;Blackman SM;Boëlle PY;Gallins PJ;Pace RG;Stonebraker JR;Accurso FJ;Clement A;Collaco JM;Dang H;Dang AT;Franca A;Gong J;Guillot L;Keenan K;Li W;Lin F;Patrone MV;Raraigh KS;Sun L;Zhou YH;O'Neal WK;Sontag MK;Levy H;Durie PR;Rommens JM;Drumm ML;Wright FA;Strug LJ;Cutting GR;Knowles MR
通讯作者：
Knowles MR
影响因子：
3.7
作者：
Kerschner, Jenny L.;Gosalia, Nehal;Harris, Ann
通讯作者：
Harris, Ann
DOI：
10.1164/rccm.201911-2199oc
发表时间：
2020-12-15
影响因子：
24.7
作者：
Deprez, Marie;Zaragosi, Laure-Emmanuelle;Barbry, Pascal
通讯作者：
Barbry, Pascal
影响因子：
64.8
作者：
Montoro DT;Haber AL;Biton M;Vinarsky V;Lin B;Birket SE;Yuan F;Chen S;Leung HM;Villoria J;Rogel N;Burgin G;Tsankov AM;Waghray A;Slyper M;Waldman J;Nguyen L;Dionne D;Rozenblatt-Rosen O;Tata PR;Mou H;Shivaraju M;Bihler H;Mense M;Tearney GJ;Rowe SM;Engelhardt JF;Regev A;Rajagopal J
通讯作者：
Rajagopal J
影响因子：
14.9
作者：
Gheldof N;Smith EM;Tabuchi TM;Koch CM;Dunham I;Stamatoyannopoulos JA;Dekker J
通讯作者：
Dekker J