Forkhead box A1 (FOXA1) and A2 (FOXA2) oppositely regulate human type 1 iodothyronine deiodinase gene in liver.
Forkhead box A1 (FOXA1) and A2 (FOXA2) oppositely regulate human type 1 iodothyronine deiodinase gene in liver.
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DOI：
10.1210/en.2011-1310
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发表时间：
2012
期刊：
影响因子：
4.8
通讯作者：
N. Kanamoto;T. Tagami;Yoriko Ueda-Sakane;Masakatsu Sone;M. Miura;A. Yasoda;N. Tamura;H. Arai
中科院分区：
文献类型：
--
作者：
N. Kanamoto;T. Tagami;Yoriko Ueda-Sakane;Masakatsu Sone;M. Miura;A. Yasoda;N. Tamura;H. Arai
I型碘甲状腺原氨酸脱碘酶(D1I)是一种催化甲状腺激素生物活性的硒酶，主要在肝脏中表达。它的表达和活性受多种因素的调节，但其转录调控的确切机制尚不清楚。在本研究中，我们分析了人类D1基因的启动子(HDIO1)，以确定在人类肝脏中普遍存在的增加D1活性的因素。缺失和突变分析表明，位于核苷酸-187和-132之间的叉头盒(Fox)A结合位点和E-box位点对肝脏中hDIO1启动子的活性是重要的。EMSA证明FOXA1和FOXA2与FOXA结合位点特异结合，上游刺激因子(USF)与E-box元件特异结合。FOXA2的过表达降低了hDIO1启动子的活性，短干扰RNA介导的FOXA2的敲除增加了hDIO1mRNA的表达。相反，USF1/2的过表达增加了hDIO1启动子的活性。短干扰RNA介导的FOXA1基因敲除可降低hDIO1基因的表达，而FOXA1和FOXA2基因的敲除可恢复hDIO1基因的表达。在没有FOXA1的情况下，hDIO1启动子对USF的反应大大减弱。综上所述，这些结果表明FOXA1和FOXA2的表达平衡调节了hDIO1在肝脏中的表达。
Type 1 iodothyronine deiodinase (D1), a selenoenzyme that catalyzes the bioactivation of thyroid hormone, is expressed mainly in the liver. Its expression and activity are modulated by several factors, but the precise mechanism of its transcriptional regulation remains unclear. In the present study, we have analyzed the promoter of human D1 gene (hDIO1) to identify factors that prevalently increase D1 activity in the human liver. Deletion and mutation analyses demonstrated that a forkhead box (FOX)A binding site and an E-box site within the region between nucleotides -187 and -132 are important for hDIO1 promoter activity in the liver. EMSA demonstrated that FOXA1 and FOXA2 specifically bind to the FOXA binding site and that upstream stimulatory factor (USF) specifically binds to the E-box element. Overexpression of FOXA2 decreased hDIO1 promoter activity, and short interfering RNA-mediated knockdown of FOXA2 increased the expression of hDIO1 mRNA. In contrast, overexpression of USF1/2 increased hDIO1 promoter activity. Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of hDIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. The response of the hDIO1 promoter to USF was greatly attenuated in the absence of FOXA1. Taken together, these results indicate that a balance of FOXA1 and FOXA2 expression modulates hDIO1 expression in the liver.