Targeted chromatin binding and histone acetylation in vivo by thyroid hormone receptor during amphibian development.
Targeted chromatin binding and histone acetylation in vivo by thyroid hormone receptor during amphibian development.
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DOI：
10.1073/pnas.260141297
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发表时间：
2000-11
影响因子：
11.1
通讯作者：
Laurent M. Sachs;Yun-Bo Shi
中科院分区：
文献类型：
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作者：
Laurent M. Sachs;Yun-Bo Shi
两栖动物的变态是由甲状腺激素（TH）诱导的与TH受体（TR）基因调控有关的显著变化。据推测，tr介导的基因调控涉及染色质重塑。在没有配体的情况下，TR可以通过招募组蛋白去乙酰化酶复合物来抑制基因表达，而配体的TR可以招募组蛋白乙酰化酶复合物来激活基因。早期的研究使我们提出了发育过程中TR的双重功能模型。在预变质蝌蚪中，未配体的TR抑制涉及组蛋白去乙酰化的转录。在变态过程中，内源性TH允许TR通过组蛋白乙酰化激活基因表达。本研究利用染色质免疫沉淀法，直接证明了TR在预变质蝌蚪体内与TH反应基因的组成性结合。我们进一步表明，TH治疗导致组蛋白去乙酰化酶从TH反应基因启动子中释放。有趣的是，在整个动物中，组蛋白乙酰化的变化与TH反应基因的表达几乎没有相关性。另一方面，在肠道和尾部，已知TH反应基因比大多数其他器官更显著地上调，我们证明TH治疗诱导基因激活和组蛋白H4乙酰化。这些数据表明，在某些组织中，组蛋白乙酰化在两栖动物发育过程中TRs的转录调控中起作用，而在其他组织中，组蛋白乙酰化水平的变化可能不起作用或仅起次要作用，这支持了TRs基因调控中存在重要的替代机制。
Amphibian metamorphosis is marked by dramatic, thyroid hormone (TH)-induced changes involving gene regulation by TH receptor (TR). It has been postulated that TR-mediated gene regulation involves chromatin remodeling. In the absence of ligand, TR can repress gene expression by recruiting a histone deacetylase complex, whereas liganded TR recruits a histone acetylase complex for gene activation. Earlier studies have led us to propose a dual function model for TR during development. In premetamorphic tadpoles, unliganded TR represses transcription involving histone deacetylation. During metamorphosis, endogenous TH allows TR to activate gene expression through histone acetylation. Here using chromatin immunoprecipitation assay, we directly demonstrate TR binding to TH response genes constitutively in vivo in premetamorphic tadpoles. We further show that TH treatment leads to histone deacetylase release from TH response gene promoters. Interestingly, in whole animals, changes in histone acetylation show little correlation with the expression of TH response genes. On the other hand, in the intestine and tail, where TH response genes are known to be up-regulated more dramatically by TH than in most other organs, we demonstrate that TH treatment induces gene activation and histone H4 acetylation. These data argue for a role of histone acetylation in transcriptional regulation by TRs during amphibian development in some tissues, whereas in others changes in histone acetylation levels may play no or only a minor role, supporting the existence of important alternative mechanisms in gene regulation by TR.