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Departments of Medicine (L.C.M., S.R.), Pediatrics (S.R.), and Human Genetics (A.M.D.), Committees on Genetics and Molecular Medicine (S.R.), The University of Chicago, Chicago, Illinois 60637; and Cancer Genetics Branch (R.L.W., P.S.M.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892
Address correspondence and requests for reprints to: Samuel Refetoff, M.D., The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}uchicago.edu.
Human skin fibroblasts are readily accessible cells for propagation in culture without transformation that can serve for direct pathophysiology studies in subjects with inherited diseases. We thus examined by quantitative fluorescent cDNA microarray analysis the effect of thyroid hormone (TH) on the expression of more than 15,000 genes in fibroblasts of two normal individuals. Fibroblasts from two subjects with resistance to thyroid hormone (RTH) due to mutations in the TH receptor-ß gene were used to confirm the specificity of the hormonal effect by the ability to discriminate between normal cells and cells with a defect in TH action. Microarray analysis identified 148 genes induced by 1.4-fold or more and five genes repressed to 0.7 or less 24 h after treatment with 2 x 10–9 M T3. Taking into account duplicate genes, these represented 91 up-regulated and five down-regulated genes, respectively. Confirmation by real-time PCR was obtained in eight of 10 induced and two of three repressed genes that were tested. Further evidence for T3-specific induction was provided by a graded dose response absent in fibroblasts from the patients with RTH. The following genes not previously known to be induced by TH were identified and validated: aldo-keto reductase family 1 C1–3, collagen type VI 
3, member RAS oncogene family brain antigen RAB3B, platelet phosphofructokinase, hypoxia-inducible factor-1, and enolase 1. These genes as well as three known to be TH regulated in other species and found in this study also in human cells (glucose transporter 1, solute carrier family 16 member 3, and basic transcription element-binding protein 1) have a variety of regulatory functions in development and metabolism. TH seems to induce these genes by initiating either genomic or nongenomic mechanisms. Surprisingly, TH-mediated down-regulation of fibroblast growth factor 7 and alcohol dehydrogenase 1B persisted in fibroblasts from patients with RTH.
This first systematic study of TH-mediated gene expression in normal human cells identifies several new TH-responsive genes and demonstrates that skin fibroblasts are suitable for the study of TH action in health and disease.
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