Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Mol Cell Biol. 2014 May;34(9):1564-75. doi: 10.1128/MCB.00129-14. Epub 2014 Feb 18.
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, NCoR(ΔID/ΔID) Src-1(-/-) mice have normal TH and TSH levels and are triiodothryonine (T(3)) sensitive at the level of the pituitary. Although absence of SRC-1 prevented T(3) activation of key hepatic gene targets, NCoR(ΔID/ΔID) Src-1(-/-) mice reacquired hepatic T(3) 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 NCoR(ΔID/ΔID) Src-1(-/-) mice, suggesting that SRC-2 is responsible for T(3) sensitivity in the absence of NCoR1 and SRC-1. Thus, T(3) 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 T(3) target genes.
甲状腺激素抵抗（RTH）是一种人类综合征，其特征是甲状腺激素（TH）和促甲状腺激素（TSH）水平升高。甲状腺激素受体β（TRβ）基因突变的小鼠和缺乏类固醇受体共激活因子 1（SRC-1）的 SRC-1（-/-）小鼠都具有类似于 RTH 的表型。相反，表达不能与 TRβ相互作用的突变核共抑制因子 1（Ncor1）等位基因的小鼠，称为 NCoRΔID，具有低 TH 水平和正常的 TSH。我们假设 SRC-1（-/-）小鼠由于缺乏共抑制因子的作用而患有 RTH。为了验证这一点，我们将 NCoRΔID 和 SRC-1（-/-）小鼠进行杂交，以产生所有细胞类型中缺乏共调节剂作用的小鼠。值得注意的是，NCoR（ΔID/ΔID）SRC-1（-/-）小鼠的 TH 和 TSH 水平正常，并且在垂体水平对三碘甲状腺原氨酸（T3）敏感。虽然缺乏 SRC-1 可阻止 T3 激活关键肝基因靶标，但 NCoR（ΔID/ΔID）SRC-1（-/-）小鼠重新获得了肝 T3 敏感性。使用体内染色质免疫沉淀测定法（ChIP）研究相关共激活因子 SRC-2，我们发现 NCoR（ΔID/ΔID）SRC-1（-/-）小鼠中 SRC-2 募集到 TR 结合区域的基因增加，这表明 SRC-2 负责在缺乏 NCoR1 和 SRC-1 的情况下 T3 敏感性。因此，T3 靶标需要 NCoR1 和 SRC-1 之间的关键平衡。此外，用 NCoRΔID 替代 NCoR1 通过增加 SRC-2 募集到 T3 靶基因来纠正 Src-1（-/-）小鼠中的 RTH。
