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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A systems approach to delineate functions of paralogous transcription factors: Role of the Yap family in the DNA damage response
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A systems approach to delineate functions of paralogous transcription factors: Role of the Yap family in the DNA damage response

机译：描述旁系转录因子功能的系统方法：Yap家族在DNA损伤反应中的作用

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摘要

Duplication of genes encoding transcription factors plays an essential role in driving phenotypic variation. Because regulation can occur at multiple levels, it is often difficult to discern how each duplicated factor achieves its regulatory specificity. In these cases, a "systems approach" may distinguish the role of each factor by integrating complementary large-scale measurements of the regulatory network. To explore such an approach, we integrate growth phenotypes, promoter binding profiles, and gene expression patterns to model the DNA damage response network controlled by the Yeast-specific AP-1 (YAP) family of transcription factors. This analysis reveals that YAP regulatory specificity is achieved by at least three mechanisms: (ⅰ) divergence of DNA-binding sequences into two subfamilies; (ⅱ) condition-specific combinatorial regulation by multiple Yap factors; and (ⅲ) interactions of Yap 1, 4, and 6 with chromatin remodeling proteins. Additional microarray experiments establish that Yap 4 and 6 regulate gene expression through interactions with the histone deacetylase, Hda1. The data further highlight differences among Yap paralogs in terms of their regulatory mode of action (activation vs. repression). This study suggests how other large TF families might be disentangled in the future.
机译：编码转录因子的基因重复在驱动表型变异中起重要作用。由于调节可以发生在多个级别，因此通常很难辨别每个重复的因素如何实现其调节特异性。在这些情况下，“系统方法”可以通过整合监管网络的补充大规模测量来区分每个因素的作用。为了探索这种方法，我们整合了生长表型，启动子结合概况和基因表达模式，以对由酵母特异性AP-1（YAP）转录因子家族控制的DNA损伤响应网络进行建模。该分析表明，YAP调节特异性是通过至少三种机制实现的：（ⅰ）DNA结合序列分成两个亚家族； （ⅱ）通过多个Yap因子进行特定条件的组合调节； （1）Yap 1、4和6与染色质重塑蛋白的相互作用。额外的微阵列实验确定Yap 4和6通过与组蛋白脱乙酰基酶Hda1的相互作用来调节基因表达。数据进一步突出了Yap旁系同源物在其调节作用方式（激活与抑制）方面的差异。这项研究表明，将来其他大型TF系列可能会被解开。

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