Tagami T, Park Y, Jameson J L
Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Biol Chem. 1999 Aug 6;274(32):22345-53. doi: 10.1074/jbc.274.32.22345.
A group of transcriptional cofactors for nuclear hormone receptors, referred to as corepressors (CoRs) and coactivators (CoAs), has been shown to induce transcriptional silencing and hormone-induced activation, respectively, of genes that contain positive hormone response elements. Transcriptional silencing by CoRs involves the recruitment of histone deacetylases (HDACs), whereas ligand-dependent activation is associated with the recruitment of CoAs, which possess or recruit histone acetyltransferases (HATs). In a reciprocal manner, negatively regulated genes are stimulated by nuclear receptors in the absence of ligand and are repressed in response to ligand binding to receptors. We show here that negative regulation of the thyroid-stimulating hormone alpha (TSHalpha) promoter by the thyroid hormone receptor (TR) involves a novel mechanism in which the recruitment of CoRs by TR is associated with transcriptional stimulation and histone acetylation. Expression of excess HDAC reverses the stimulation mediated by the TR.CoR complex, consistent with a pivotal role for acetylation in this event. Addition of the ligand, 3,5,3'-triiodothyronine (T3), induces transcriptional repression of the TSHalpha promoter and is associated with the loss of histone acetylation. T3-dependent repression is blocked by phosphorylation of cAMP response element binding protein, or by inhibition of HDAC, indicating that receptor action is subverted by maneuvers that stimulate histone acetylation of the target gene. We propose that negative regulation of a subset of genes by TR involves the active exchange of CoRs and CoAs with intrinsic promoter regulatory elements that normally strongly induce histone acetylation and transcriptional activation.
一组被称为共抑制因子（CoRs）和共激活因子（CoAs）的核激素受体转录辅因子，已被证明分别诱导含有正向激素反应元件的基因发生转录沉默和激素诱导的激活。CoRs介导的转录沉默涉及组蛋白去乙酰化酶（HDACs）的募集，而配体依赖性激活则与共激活因子的募集有关，共激活因子具有或募集组蛋白乙酰转移酶（HATs）。相反，负调控基因在无配体时被核受体刺激，而在配体与受体结合时被抑制。我们在此表明，甲状腺激素受体（TR）对促甲状腺激素α（TSHα）启动子的负调控涉及一种新机制，即TR募集共抑制因子与转录刺激和组蛋白乙酰化相关。过量HDAC的表达逆转了TR - CoR复合物介导的刺激，这与乙酰化在该过程中的关键作用一致。添加配体3,5,3'-三碘甲状腺原氨酸（T3）可诱导TSHα启动子的转录抑制，并与组蛋白乙酰化的丧失相关。cAMP反应元件结合蛋白的磷酸化或HDAC的抑制可阻断T3依赖性抑制，表明刺激靶基因组蛋白乙酰化的操作可颠覆受体的作用。我们提出，TR对一部分基因的负调控涉及共抑制因子和共激活因子与内在启动子调控元件的主动交换，这些元件通常强烈诱导组蛋白乙酰化和转录激活。
