Novel regulatory role for human Acf1 in transcriptional repression of vitamin D3 receptor-regulated genes
Novel regulatory role for human Acf1 in transcriptional repression of vitamin D3 receptor-regulated genes
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DOI：
10.1210/me.2007-0095
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发表时间：
2007-08-01
影响因子：
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通讯作者：
Chakravarti, Debabrata
中科院分区：
文献类型：
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作者：
Ewing, Amy K.;Attner, Michelle;Chakravarti, Debabrata
激素和维生素在调节核激素受体（NR）超家族成员的转录活性中起着不可或缺的作用。核受体辅阻遏蛋白（N-CoR）是非配体核受体抑制转录的关键蛋白。为了分离激素信号通路的新组分，我们使用酵母双杂交筛选并鉴定了人类ATP利用染色质组装和重塑因子1（hAcf 1）作为N-CoR相互作用蛋白。一个以前未被认识到的功能hAcf 1在哺乳动物细胞中的常染色质基因的抑制被发现：hAcf 1在激素的反应性和特定的II类NR调节基因的转录抑制中起着关键作用。首先，激素处理导致hAcf 1从其靶基因启动子显著释放。第二，hAcf 1对于分别在维生素D3调节的IGF结合蛋白3和核因子-κ B配体基因启动子的受体激活剂中稳定内源性维生素D受体-N-CoR阻遏复合物和N-CoR本身是至关重要的。第三，RNA干扰介导的hAcf 1或维生素D3处理的减少对这些基因中的组蛋白修饰谱和组蛋白占有率有不同的影响。总之，这些结果表明，hAcf 1在特定的NR调控基因的转录抑制中具有关键作用，并表明hAcf 1释放和组蛋白H3和H4驱逐是在转录诱导的基因激活的新机制。
Hormones and vitamins play integral roles in modulating transcriptional activity of members of the nuclear hormone receptor (NR) superfamily. The nuclear receptor corepressor protein (N-CoR) is essential for the transcriptional repression by unliganded NRs. In an attempt to isolate novel components of the hormone signaling pathway, we used a yeast two-hybrid screen and identified human ATP-utilizing chromatin assembly and remodeling factor 1 (hAcf1) as an N-CoR interacting protein. A previously unrecognized function of hAcf1 in the repression of euchromatic genes in mammalian cells was found: hAcf1 plays key roles in the hormone responsiveness and in the transcriptional repression of specific class II NR-regulated genes. First, hormone treatment causes a significant release of hAcf1 from its target gene promoters. Second, hAcf1 is crucial for stabilizing the endogenous vitamin D receptor-N-CoR repression complex and N-CoR itself, in the vitamin D3-regulated IGF binding protein 3 and receptor activator of nuclear factor- kappa B ligand gene promoters, respectively. Third, RNA interference-mediated reduction of hAcf1 or vitamin D3 treatment differentially affects the histone modification profile and the histone occupancy in these genes. Together, these results establish that hAcf1 has a critical role in the transcriptional repression of specific NR-regulated genes and indicate that hAcf1 release and histone H3 and H4 eviction are novel mechanisms in hormone-induced gene activation.