Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice.
Little is known about the overall patterns of thyroid hormone (Th)-mediated gene regulation by the main Th receptor (Tr) isoforms, Tr-alpha and Tr-beta, in vivo. We used 48 complementary DNA microarrays to examine hepatic gene expression profiles of wild-type and Thra and Thrb knockout mice under different Th conditions: no treatment, treatment with 3,3',5-triiodothyronine (T(3)), Th-deprivation using propylthiouracil (PTU), and treatment with a combination of PTU and T(3). Hierarchical clustering analyses showed that positively regulated genes fit into three main expression patterns. In addition, only a subpopulation of target genes repressed basal transcription in the absence of ligand. Interestingly, Thra and Thrb knockout mice showed similar gene expression patterns to wild-type mice, suggesting that these isoforms co-regulate most hepatic target genes. Differences in the gene expression patterns of Thra/Thrb double-knockout mice and Th-deprived wild-type mice show that absence of receptor and of hormone can have different effects. This large-scale study of hormonal regulation reveals the functions of Th and of Tr isoforms in the regulation of gene expression patterns.
Yen
Paul M
PM
Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Room 8D12, Building 10, Bethesda, MD 20892, USA. pauly@intra.niddk.nih.gov
Feng
Xu
X
Flamant
Frederic
F
Chen
Yidong
Y
Walker
Robert L
RL
Weiss
Roy E
RE
Chassande
Olivier
O
Samarut
Jacques
J
Refetoff
Samuel
S
Meltzer
Paul S
PS
D000818:Animals; D016000:Cluster Analysis; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005838:Genotype; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011441:Propylthiouracil / Q000494:pharmacology; D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry / Q000235:genetics*; D014285:Triiodothyronine, Reverse / Q000494:pharmacology; D015854:Up-Regulation
D018076:DNA, Complementary; D008024:Ligands; D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014285:Triiodothyronine, Reverse; D011441:Propylthiouracil