Forkhead Box A1 (FOXA1) and A2 (FOXA2) Oppositely Regulate Human Type 1 Iodothyronine Deiodinase Gene in Liver

Naotetsu Kanamoto, Tetsuya Tagami, Yoriko Ueda-Sakane, Masakatsu Sone, Masako Miura, Akihiro Yasoda, Naohisa Tamura, Hiroshi Arai, Kazuwa Nakao
2012 Endocrinology  
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
more » ... at a forkhead box (FOX)A binding site and an E-box site within the region between nucleotides Ϫ187 and Ϫ132 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. (Endocrinology 153: 492-500, 2012) T hyroid hormone activation and inactivation are mediated by three selenoenzymes, type 1 iodothyronine deiodinase (D1), D2, and D3. D1 and D2 catalyze the conversion of T 4 to T 3 via removal of outerring iodine (1). The human D1 gene (hDIO1) is expressed in the liver, kidney, thyroid, and pituitary (2). The D2 gene is expressed in the central nervous system, pituitary, heart, and skeletal muscle, but it is absent in the liver (1). The D3 gene is expressed in the central nervous system and placenta, and it is involved in thyroid hormone inactivation by mediating the removal of innerring iodine. Unlike D2, D1 activity is considered to be regulated predominantly at the pretranslational level. The expression and activity of D1 are modulated by a variety of factors. T 3 induces the expression of hDIO1 via two thyroid hormone responsive elements within its promoter (3), and nuclear factor B induced by TNF␣ inhibits the T 3 -dependent induction of D1 (4). However, the precise mechanism of the transcriptional regulation of hDIO1 expression remains unclear. In this study, we sought to identify factors that increased D1 activity in the liver, a main organ that expresses hDIO1. We assessed the promoter activity of the 5-kb 5Ј-flanking region of hDIO1 and characterized regulatory element-binding proteins within this region. In this study, we identify responsive elements for the forkhead box (FOX) transcription factors FOXA1/FOXA2 and the ba-
doi:10.1210/en.2011-1310 pmid:22067325 fatcat:sn7q6zp7b5ex5dp73vh2w3zq3q