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 (hDIO1) gene 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 −187 and −132 bp are important for hDIO1 gene 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 gene promoter activity, and short interfering RNA-mediated knockdown of FOXA2 increased the expression of hDIO1 gene mRNA. In contrast, overexpression of USF1/2 increased hDIO1 gene promoter activity. Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of hDIO1 gene mRNA, but knockdown of both FOXA1 and FOXA2 restored it. The response of the hDIO1 gene 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 gene expression in the liver.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.
05 - 09 May 2012
European Society of Endocrinology