The functional importance of telomere clustering: global changes in gene expression result from SIR factor dispersion.
The functional importance of telomere clustering: global changes in gene expression result from SIR factor dispersion.
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端粒聚类的功能重要性：基因表达的全局变化是由 SIR 因子分散造成的。
DOI：
10.1101/gr.083881.108
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发表时间：
2009
期刊：
影响因子：
7
通讯作者：
S. Gasser
中科院分区：
文献类型：
--
作者：
A. Taddei;G. van Houwe;S. Nagai;Ionas Erb;E. van Nimwegen;S. Gasser
出芽酵母端粒和隐蔽的交配型基因座在核膜处富集，形成隔离沉默信息调节因子（SIR因子）的焦点，就像高等真核生物中的异染色质中心隔离HP1一样。在这里，我们研究了此类子区室对调节全基因组转录的影响。我们表明，亚端粒报告基因抑制的效率不仅取决于顺式作用元件招募 SIR 因子的强度，还取决于 SIR 在此类核周病灶中的积累。为了监测破坏这种亚核区室的影响，我们在消除端粒锚定的条件下进行了微阵列分析，同时保留了 SIR 复合物的完整性。我们发现 60 个基因可重复地失调。在表达增加的基因中，22% 位于端粒 20 kb 范围内，证实端粒的核膜 (NE) 关联有助于抑制天然亚端粒基因。相反，下调的基因座分布在所有染色体上。这种异位抑制的一半是 SIR 复合物依赖性的。我们得出的结论是，尽管存在“抗沉默”机制，但释放的 SIR 因子可以混杂地抑制非端粒基因的转录。生物信息学分析表明，带有 PAC（RNA 聚合酶 A 和 C 启动子）或 Abf1 结合序列的启动子会因 SIR 因子的错误定位而持续下调。因此，SIR 的正常端粒隔离既有利于亚端粒抑制，又可防止不同启动子子集的混杂效应。这表明基因表达模式可以通过改变结合抑制因子的重复DNA序列的空间分布来调节。
Budding yeast telomeres and cryptic mating-type loci are enriched at the nuclear envelope, forming foci that sequester silent information regulators (SIR factors), much as heterochromatic chromocenters in higher eukaryotes sequester HP1. Here we examine the impact of such subcompartments for regulating transcription genome-wide. We show that the efficiency of subtelomeric reporter gene repression depends not only on the strength of SIR factor recruitment by cis-acting elements, but also on the accumulation of SIRs in such perinuclear foci. To monitor the effects of disrupting this subnuclear compartment, we performed microarray analyses under conditions that eliminate telomere anchoring, while preserving SIR complex integrity. We found 60 genes reproducibly misregulated. Among those with increased expression, 22% were within 20 kb of a telomere, confirming that the nuclear envelope (NE) association of telomeres helps repress natural subtelomeric genes. In contrast, loci that were down-regulated were distributed over all chromosomes. Half of this ectopic repression was SIR complex dependent. We conclude that released SIR factors can promiscuously repress transcription at nontelomeric genes despite the presence of "anti-silencing" mechanisms. Bioinformatic analysis revealed that promoters bearing the PAC (RNA Polymerase A and C promoters) or Abf1 binding consenses are consistently down-regulated by mislocalization of SIR factors. Thus, the normal telomeric sequestration of SIRs both favors subtelomeric repression and prevents promiscuous effects at a distinct subset of promoters. This demonstrates that patterns of gene expression can be regulated by changing the spatial distribution of repetitive DNA sequences that bind repressive factors.
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