RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.
RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.
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DOI：
10.1038/jid.2014.519
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发表时间：
2015-04
影响因子：
6.5
通讯作者：
Zhang, Jennifer Y.
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoling;Jin, Jane Y.;Wu, Joseph;Qin, Xiaoxia;Streilein, Robert;Hall, Russell P.;Zhang, Jennifer Y.
表皮中JunB转录因子缺失的小鼠表现出银屑病样炎症。这些发现与人类的相关性以及介导JunB功能的机制尚未完全了解。在此，我们证明通过基因沉默或显性负性突变体的过表达使JunB功能受损会增加人角质形成细胞的增殖，但会降低细胞屏障功能。RNA测序显示超过500个基因受JunB功能缺失的影响，其中包括一系列与银屑病相关的促炎分子的上调。其中有TNFα、CCL2、CXCL10、IL6R和SQSTM1（一种参与NF - κB激活的衔接蛋白）。染色质免疫沉淀测序（ChIP - Seq）和基因报告分析表明，JunB通过结合位于SQSTM1转录起始位点上游约2kb处的一个共有AP - 1顺式元件直接抑制SQSTM1。与JunB功能缺失类似，SQSTM1过表达诱导TNFα、CCL2和CXCL10。相反，通过突变型IκBα进行基因抑制或用吡咯烷二硫代氨基甲酸（PDTC）进行药物抑制NF - κB，可阻止JunB缺失诱导的细胞因子（但不包括IL6R）产生。综上所述，我们的研究结果表明，JunB通过直接和间接机制控制表皮生长、屏障形成和促炎反应，确定SQSTM1是JunB抑制NF - κB依赖性炎症的关键介质。
Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here, we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss-of-function which included an upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were TNFα, CCL2, CXCL10, IL6R and SQSTM1, an adaptor protein involved in NF-κB activation. ChIP-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 through binding to a consensus AP-1 cis-element located around 2 Kb upstream of SQSTM1-trasncription start site. Similar to JunB loss-of-function, SQSTM1-overexpression induced TNFα, CCL2 and CXCL10. Conversely, NF-κB-inhibition genetically with a mutant IκBα or pharmacologically with PDTC prevented cytokine, but not IL6R, induction by JunB-deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB-suppression of NF-κB-dependent inflammation.
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