The stress response factors Yap6, Cin5, Phd1, and Skn7 direct targeting of the conserved co-repressor Tup1-Ssn6 in S. cerevisiae.
The stress response factors Yap6, Cin5, Phd1, and Skn7 direct targeting of the conserved co-repressor Tup1-Ssn6 in S. cerevisiae.
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DOI：
10.1371/journal.pone.0019060
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发表时间：
2011-04-28
期刊：
影响因子：
3.7
通讯作者：
Buck MJ
中科院分区：
文献类型：
--
作者：
Hanlon SE;Rizzo JM;Tatomer DC;Lieb JD;Buck MJ
在发育过程中或对环境变化的反应中维持转录组的适当表达需要在转录调控因子与激活和抑制功能之间保持微妙的平衡。出芽酵母转录共抑制因子Tup1-Ssn6是研究多细胞真核生物中类似抑制因子复合物的一个模型。Tup1- ssn6不直接结合DNA，而是由一个或多个DNA结合蛋白（称为Tup1招募蛋白）引导到单个启动子上。这种功能结构允许Tup1-Ssn6调节对各种细胞应激反应所需的基因表达。为了了解Tup1-Ssn6复合物的靶向性，我们通过ChIP-chip确定了Tup1和Ssn6的基因组分布。我们发现，Tup1- ssn6结合的大多数位点不能用与已知的招募辅因子共占用来解释，并且删除单个已知的Tup1招募者并没有显著改变Tup1的结合谱。这些观察结果表明，新的Tup1招募蛋白仍有待发现，而Tup1的招募通常依赖于多个招募辅助因子。为了鉴定新的招募蛋白，我们计算筛选了与观察到的Tup1-Ssn6基因组分布相似的结合模式的因子。四种候选基因Cin5、Skn7、Phd1和Yap6都与应激反应基因调控有关，实验证实它们与Tup1和/或Ssn6存在物理相互作用。将这些新的招募辅因子与先前表征的辅因子结合起来，现在解释了整个基因组中大部分的Tup1靶向，并扩展了我们对Tup1- ssn6定向到其靶标的机制的理解。
Maintaining the proper expression of the transcriptome during development or in response to a changing environment requires a delicate balance between transcriptional regulators with activating and repressing functions. The budding yeast transcriptional co-repressor Tup1-Ssn6 is a model for studying similar repressor complexes in multicellular eukaryotes. Tup1-Ssn6 does not bind DNA directly, but is directed to individual promoters by one or more DNA-binding proteins, referred to as Tup1 recruiters. This functional architecture allows the Tup1-Ssn6 to modulate the expression of genes required for the response to a variety of cellular stresses. To understand the targeting or the Tup1-Ssn6 complex, we determined the genomic distribution of Tup1 and Ssn6 by ChIP-chip. We found that most loci bound by Tup1-Ssn6 could not be explained by co-occupancy with a known recruiting cofactor and that deletion of individual known Tup1 recruiters did not significantly alter the Tup1 binding profile. These observations suggest that new Tup1 recruiting proteins remain to be discovered and that Tup1 recruitment typically depends on multiple recruiting cofactors. To identify new recruiting proteins, we computationally screened for factors with binding patterns similar to the observed Tup1-Ssn6 genomic distribution. Four top candidates, Cin5, Skn7, Phd1, and Yap6, all known to be associated with stress response gene regulation, were experimentally confirmed to physically interact with Tup1 and/or Ssn6. Incorporating these new recruitment cofactors with previously characterized cofactors now explains the majority of Tup1 targeting across the genome, and expands our understanding of the mechanism by which Tup1-Ssn6 is directed to its targets.
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