Epigenetic mechanism of rRNA gene silencing: Temporal order of NoRC-mediated histone modification, chromatin remodeling, and DNA methylation
Epigenetic mechanism of rRNA gene silencing: Temporal order of NoRC-mediated histone modification, chromatin remodeling, and DNA methylation
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DOI：
10.1128/mcb.25.7.2539-2546.2005
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发表时间：
2005-04-01
影响因子：
5.3
通讯作者：
Grummt, I
中科院分区：
文献类型：
--
作者：
Santoro, R;Grummt, I
表观遗传控制机制使真核生物中约一半的rRNA基因沉默。以前的研究已经证明，募集NoRC，一个SNF 2 h的重塑复合物，沉默rRNA基因转录。NoRC介导组蛋白H4去乙酰化、组蛋白H3-Lys 9二甲基化和从头DNA甲基化，从而在rRNA基因启动子处建立异染色质特征。在这里，我们表明，任何这些活动的抑制都是NoRC依赖的沉默，表明这些过程是密切相关的。我们已经研究了基因沉默过程中rRNA基因启动子的表观遗传事件的时间顺序，并证明TTF-I对NoRC的招募是组蛋白H4脱乙酰化和组蛋白H3-Lys 9二甲基化的先决条件。抑制组蛋白去乙酰化可防止DNA甲基化，而抑制DNA甲基化不影响组蛋白修饰。重要的是，依赖ATP的染色质重塑是rRNA基因启动子上游控制元件内特定CpG二核苷酸甲基化所必需的，这种修饰损害了preinitiation复合物的形成。这项研究的结果揭示了一个明确的层次表观遗传事件，控制从头DNA甲基化，并导致RNA基因沉默。
Epigenetic control mechanisms silence about half of the rRNA genes in eukaryotes. Previous studies have demonstrated that recruitment of NoRC, a SNF2h-containing remodeling complex, silences rRNA gene transcription. NoRC mediates histone H4 deacetylation, histone H3-Lys9 dimethylation, and de novo DNA methylation, thus establishing heterochromatic features at the rRNA gene promoter. Here we show that inhibition of any of these activities alleviates NoRC-dependent silencing, indicating that these processes are intimately linked. We have studied the temporal order of epigenetic events at the rRNA gene promoter during gene silencing and demonstrate that recruitment of NoRC by TTF-I is a prerequisite for the deacetylation of histone H4 and the dimethylation of histone H3-Lys9. Inhibition of histone deacetylation prevents DNA methylation, while inhibition of DNA methylation does not affect histone modification. Importantly, ATP-dependent chromatin remodeling is required for methylation of a specific CpG dinucleotide within the upstream control element of the rRNA gene promoter, and this modification impairs preinitiation complex formation. The results of this study reveal a clear hierarchy of epigenetic events that control de novo DNA methylation and lead to silencing of RNA genes.