Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region.
The transcription of the human UCP3 (uncoupling protein-3) gene in skeletal muscle is tightly regulated by metabolic signals related to fatty acid availability. However, changes in thyroid status also modulate UCP3 gene expression, albeit by unknown mechanisms. We created transgenic mice bearing the entire human UCP3 gene to investigate the effect of thyroid hormones on human UCP3 gene expression. Treatment of human UCP3 transgenic mice with thyroid hormones induced the expression of the human gene in skeletal muscle. In addition, transient transfection experiments demonstrate that thyroid hormones activate the transcription of the human UCP3 gene promoter when MyoD and the TR (thyroid hormone receptor) were co-transfected. The action of thyroid hormones on UCP3 gene transcription is mediated by the binding of the TR to a proximal region in the UCP3 gene promoter that contains a direct repeat structure. An intact DNA sequence of this site is required for thyroid hormone responsiveness and TR binding. Chromatin immunoprecipitation assays revealed that the TR binds this element in vivo. The murine Ucp3 gene promoter was also dependent on MyoD and responsive to thyroid hormone in transient transfection assays. However, it was much less sensitive to thyroid hormone than the human UCP3 promoter. In summary, UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region. Such regulation suggests a link between UCP3 gene expression and the effects of thyroid hormone on mitochondrial function in skeletal muscle.
Solanes
Gemma
G
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avda Diagonal 645, E-08028 Barcelona, Spain. gsolanes@ub.edu
Pedraza
Neus
N
Calvo
Verónica
V
Vidal-Puig
Antonio
A
Lowell
Bradford B
BB
Villarroya
Francesc
F
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D005508:Food Deprivation / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007473:Ion Channels; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D013217:Starvation / Q000235:genetics; D013963:Thyroid Hormones / Q000494:pharmacology*; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3