Thyroid Hormone Signaling In Vivo Requires a Balance between Coactivators and Corepressors |
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Authors: | Kristen R. Vella Preeti Ramadoss Ricardo H. Costa-e-Sousa Inna Astapova Felix D. Ye Kaila A. Holtz Jamie C. Harris Anthony N. Hollenberg |
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Affiliation: | Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA |
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Abstract: | Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TRβ) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1−/− mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TRβ, termed NCoRΔID, have low TH levels and normal TSH. We hypothesized that Src-1−/− mice have RTH due to unopposed corepressor action. To test this, we crossed NCoRΔID and Src-1−/− mice to create mice deficient for coregulator action in all cell types. Remarkably, NCoRΔID/ΔIDSrc-1−/− mice have normal TH and TSH levels and are triiodothryonine (T3) sensitive at the level of the pituitary. Although absence of SRC-1 prevented T3 activation of key hepatic gene targets, NCoRΔID/ΔIDSrc-1−/− mice reacquired hepatic T3 sensitivity. Using in vivo chromatin immunoprecipitation assays (ChIP) for the related coactivator SRC-2, we found enhanced SRC-2 recruitment to TR-binding regions of genes in NCoRΔID/ΔIDSrc-1−/− mice, suggesting that SRC-2 is responsible for T3 sensitivity in the absence of NCoR1 and SRC-1. Thus, T3 targets require a critical balance between NCoR1 and SRC-1. Furthermore, replacement of NCoR1 with NCoRΔID corrects RTH in Src-1−/− mice through increased SRC-2 recruitment to T3 target genes. |
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