Transcriptional Regulation of ZNF638 in Thermogenic Cells by the cAMP Response Element Binding Protein in Male Mice
Transcriptional Regulation of ZNF638 in Thermogenic Cells by the cAMP Response Element Binding Protein in Male Mice
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DOI：
10.1210/js.2019-00238
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发表时间：
2019-12-01
影响因子：
4.1
通讯作者：
Mueller, Elisabetta
中科院分区：
文献类型：
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作者：
Perie, Luce;Verma, Narendra;Mueller, Elisabetta
锌指因子参与多种细胞过程，包括脂肪组织分化和产热。我们以前已经证明，锌指蛋白638（ZNF 638）是一种转录辅激活因子，在体外作为脂肪形成的早期调节剂。在这项研究中，我们首次发现，在体内，ZNF 638选择性地富集在成熟的棕色和皮下脂肪组织以及完全分化的产热脂肪细胞中。此外，基因表达研究表明，ZNF 638上调cAMP调节剂在体外和冷暴露和药理刺激的β-肾上腺素能信号在体内。对ZNF 638基因上游调控区的计算机分析在ZNF 638转录起始位点的500 bp内鉴定出两个推定的cAMP反应元件。详细的分子分析，包括EMSA和染色质免疫沉淀试验表明，cAMP反应元件结合蛋白（CREB）结合这些cAMP反应元件区域的ZNF 638启动子，和功能研究表明，CREB是必要的，足以调节ZNF 638的转录水平。综上所述，这些结果表明，ZNF 638选择性地表达在成熟的产热脂肪细胞和组织中，并且其对促进产热的经典刺激的诱导是通过CREB信号转导介导的，这表明ZNF 638在棕色和米色脂肪组织中可能具有新的作用。版权所有（C）2019内分泌学会
Zinc finger factors are implicated in a variety of cellular processes, including adipose tissue differentiation and thermogenesis. We have previously demonstrated that zinc finger protein 638 (ZNF638) is a transcriptional coactivator acting as an early regulator of adipogenesis in vitro. In this study, we show, to our knowledge for the first time, that, in vivo, ZNF638 abounds selectively in mature brown and subcutaneous fat tissues and in fully differentiated thermogenic adipocytes. Furthermore, gene expression studies revealed that ZNF638 is upregulated by cAMP modulators in vitro and by cold exposure and by pharmacological stimulation of p-adrenergic signaling in vivo. In silico analysis of the upstream regulatory region of the ZNF638 gene identified two putative cAMP response elements within 500 bp of the ZNF638 transcription start site. Detailed molecular analysis involving EMSA and chromatin immunoprecipitation assays demonstrated that cAMP response element binding protein (CREB) binds to these cAMP response element regions of the ZNF638 promoter, and functional studies revealed that CREB is necessary and sufficient to regulate the levels of ZNF638 transcripts. Taken together, these results demonstrate that ZNF638 is selectively expressed in mature thermogenic adipocytes and tissues and that its induction in response to classic stimuli that promote heat generation is mediated via CREB signaling, pointing to a possible novel role of ZNF638 in brown and beige fat tissues. Copyright (C) 2019 Endocrine Society