Hepatocyte nuclear factor 4alpha contributes to thyroid hormone homeostasis by cooperatively regulating the type 1 iodothyronine deiodinase gene with GATA4 and Kruppel-like transcription factor 9.
Type 1 iodothyronine deiodinase (Dio1), a selenoenzyme catalyzing the bioactivation of thyroid hormone, is highly expressed in the liver. Dio1 mRNA and enzyme activity levels are markedly reduced in the livers of hepatocyte nuclear factor 4alpha (HNF4alpha)-null mice, thus accounting for its liver-specific expression. Consistent with this deficiency, serum T4 and rT3 concentrations are elevated in these mice compared with those in HNF4alpha-floxed control littermates; however, serum T3 levels are unchanged. Promoter analysis of the mouse Dio1 gene demonstrated that HNF4alpha plays a key role in the transactivation of the mouse Dio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4alpha site (direct repeat 1 [TGGACAAAGGTGC]; HNF4alpha-RE) is crucial for transactivation of the mouse Dio1 gene by HNF4alpha. Mouse Dio1 is also stimulated by thyroid hormone signaling, but a direct role for thyroid hormone receptor action has not been reported. We also showed that thyroid hormone-inducible Krüppel-like factor 9 (KLF9) stimulates the mouse Dio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4alpha-RE. Furthermore, KLF9 functions together with HNF4alpha and GATA4 to synergistically activate the mouse Dio1 promoter, suggesting that Dio1 is regulated by thyroid hormone in the mouse through an indirect mechanism requiring prior KLF9 induction. In addition, we showed that physical interactions between the C-terminal zinc finger domain (Cf) of GATA4 and activation function 2 of HNF4alpha and between the basic domain adjacent to Cf of GATA4 and a C-terminal domain of KLF9 are both required for this synergistic response. Taken together, these results suggest that HNF4alpha regulates thyroid hormone homeostasis through transcriptional regulation of the mouse Dio1 gene with GATA4 and KLF9.
Ohguchi
Hiroto
H
Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
Tanaka
Toshiya
T
Uchida
Aoi
A
Magoori
Kenta
K
Kudo
Hiromi
H
Kim
Insook
I
Daigo
Kenji
K
Sakakibara
Iori
I
Okamura
Masashi
M
Harigae
Hideo
H
Sasaki
Takeshi
T
Osborne
Timothy F
TF
Gonzalez
Frank J
FJ
Hamakubo
Takao
T
Kodama
Tatsuhiko
T
Sakai
Juro
J
D000818:Animals; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007453:Iodide Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D013963:Thyroid Hormones / Q000378:metabolism*; D015533:Transcriptional Activation
D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C484171:Gata4 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C489676:KLF9 protein, human; C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D013963:Thyroid Hormones; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase