Ni Li, Bruce Can, Hart Christopher, Leigh-Bell Justine, Gelperin Daniel, Umansky Lara, Gerstein Mark B, Snyder Michael
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA.
Genes Dev. 2009 Jun 1;23(11):1351-63. doi: 10.1101/gad.1781909.
Complex biological processes are often regulated, at least in part, by the binding of transcription factors to their targets. Recently, considerable effort has been made to analyze the binding of relevant factors to the suite of targets they regulate, thereby generating a regulatory circuit map. However, for most studies the dynamics of binding have not been analyzed, and thus the temporal order of events and mechanisms by which this occurs are poorly understood. We globally analyzed in detail the temporal order of binding of several key factors involved in the salt response of yeast to their target genes. Analysis of Yap4 and Sko1 binding to their target genes revealed multiple temporal classes of binding patterns: (1) constant binding, (2) rapid induction, (3) slow induction, and (4) transient induction. These results demonstrate that individual transcription factors can have multiple binding patterns and help define the different types of temporal binding patterns used in eukaryotic gene regulation. To investigate these binding patterns further, we also analyzed the binding of seven other key transcription factors implicated in osmotic regulation, including Hot1, Msn1, Msn2, Msn4, Skn7, and Yap6, and found significant coassociation among the different factors at their gene targets. Moreover, the binding of several key factors was correlated with distinct classes of Yap4- and Sko1-binding patterns and with distinct types of genes. Gene expression studies revealed association of Yap4, Sko1, and other transcription factor-binding patterns with different gene expression patterns. The integration and analysis of binding and expression information reveals a complex dynamic and hierarchical circuit in which specific combinations of transcription factors target distinct sets of genes at discrete times to coordinate a rapid and important biological response.
复杂的生物过程通常至少部分地受到转录因子与其靶标的结合调控。最近，人们付出了巨大努力来分析相关因子与其所调控的一系列靶标的结合情况，从而生成调控电路图。然而，对于大多数研究而言，结合动力学尚未得到分析，因此事件发生的时间顺序及其机制仍知之甚少。我们全面详细地分析了酵母盐反应中涉及的几个关键因子与其靶基因结合的时间顺序。对Yap4和Sko1与其靶基因的结合分析揭示了多种时间类型的结合模式：（1）持续结合，（2）快速诱导，（3）缓慢诱导，以及（4）瞬时诱导。这些结果表明，单个转录因子可以具有多种结合模式，并有助于定义真核基因调控中使用的不同类型的时间结合模式。为了进一步研究这些结合模式，我们还分析了其他七个与渗透调节有关的关键转录因子的结合情况，包括Hot1、Msn1、Msn2、Msn4、Skn7和Yap6，发现不同因子在其基因靶标处存在显著的共关联。此外，几个关键因子的结合与Yap4和Sko1结合模式的不同类别以及不同类型的基因相关。基因表达研究揭示了Yap4、Sko1和其他转录因子结合模式与不同基因表达模式的关联。结合和表达信息的整合与分析揭示了一个复杂的动态分层电路，其中转录因子的特定组合在离散时间靶向不同的基因集，以协调快速而重要的生物学反应。
