Koenig R J
Division of Endocrinology, University of Michigan Medical Center, Ann Arbor 48109-0678, USA.
Thyroid. 1998 Aug;8(8):703-13. doi: 10.1089/thy.1998.8.703.
In the absence of triiodothyronine (T3), thyroid hormone receptors (TRs) repress transcription of many genes; in the presence of T3, TRs activate transcription of those same genes. Both of these events are dependent on interactions between TRs and other nuclear proteins. TRs bind to specific DNA sequences, generally found in the 5' flanking regions of target genes. In the unliganded state, TRs interact with one of several corepressor proteins. These proteins, in turn, interact with a series of other proteins, which includes histone deacetylases. Histone deacetylation tightens chromatin structure, thus impairing access of critical transcription factors and thereby repressing transcription. In addition, corepressors may invoke mechanisms of gene repression independent of histone deacetylation. The binding of T3 causes a conformational change in the TR that results in release of the corepressor and recruitment of coactivator proteins. Several coactivator proteins appear to bind the ligand-occupied TR as a multiprotein complex. Opposite to corepressors, coactivators acetylate histones, thereby loosening chromatin structure and facilitating access of key transcription factors. Again, mechanisms independent of histone acetylation also may be involved. Overall, gene activation by T3 is a two-step process; removal of active repression, and induction of transcription to levels above the "neutral" state.
在没有三碘甲状腺原氨酸（T3）的情况下，甲状腺激素受体（TRs）会抑制许多基因的转录；在有T3存在时，TRs会激活这些相同基因的转录。这两种情况都依赖于TRs与其他核蛋白之间的相互作用。TRs与特定的DNA序列结合，这些序列通常位于靶基因的5'侧翼区域。在未结合配体的状态下，TRs与几种共抑制蛋白之一相互作用。这些蛋白进而与一系列其他蛋白相互作用，其中包括组蛋白脱乙酰酶。组蛋白去乙酰化会使染色质结构收紧，从而妨碍关键转录因子的进入，进而抑制转录。此外，共抑制蛋白可能会引发独立于组蛋白去乙酰化的基因抑制机制。T3的结合会导致TR发生构象变化，从而导致共抑制蛋白的释放和共激活蛋白的募集。几种共激活蛋白似乎以多蛋白复合物的形式结合被配体占据的TR。与共抑制蛋白相反，共激活蛋白会使组蛋白乙酰化，从而使染色质结构松弛并促进关键转录因子的进入。同样，也可能涉及独立于组蛋白乙酰化的机制。总体而言，T3介导的基因激活是一个两步过程：去除活性抑制，并将转录诱导至高于“中性”状态的水平。
