The interaction between nuclear receptor corepressor and histone deacetylase 3 regulates both positive and negative thyroid hormone action in vivo.
Thyroid hormone (TH) plays a critical role in development, growth, and metabolism by binding to nuclear TH receptors to modulate gene expression. In the absence of TH, TH receptors repress genes that are TH-activated by recruiting the nuclear receptor corepressor (NCoR), which exists in a tight complex with histone deacetylase 3 (HDAC3). Here we explored the actions of TH in the deacetylase activating domain mutant (DADm) mouse, whose NCoR-HDAC3 interaction is genetically disrupted. Several TH-activated genes were derepressed in the liver of euthyroid and hypothyroid DADm mice, consistent with the corepressor paradigm and a critical role of the NCoR-HDAC3 interaction in basal repression. The role of corepressors in genes that are down-regulated by TH is less well understood. Remarkably, circulating TSH levels were increased in euthyroid DADm mice, and the pituitary expression of TSHalpha, a classic TH-down-regulated gene, was modestly but significantly elevated regardless of TH status. Thus, the NCoR interaction with HDAC3 modulates expression of both positively- and negatively-regulated genes by TH in vivo.
You
Seo-Hee
SH
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Liao
Xiaohui
X
Weiss
Roy E
RE
Lazar
Mitchell A
MA
D047369:Chromatin Immunoprecipitation; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010902:Pituitary Gland / Q000378:metabolism; D011485:Protein Binding; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000097:blood*; D014284:Triiodothyronine / Q000097:blood*; D000099186:Histone Deacetylase 3
D056970:Co-Repressor Proteins; D006655:Histone Deacetylases; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; D000099186:Histone Deacetylase 3