Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function.
Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function.
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DOI：
10.1038/nature10985
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发表时间：
2012-04-11
期刊：
影响因子：
64.8
通讯作者：
Lieb, Jason D.
中科院分区：
文献类型：
--
作者：
Lickwar, Colin R.;Mueller, Florian;Hanlon, Sean E.;McNally, James G.;Lieb, Jason D.
动态获取遗传信息是生物体发育和环境响应的核心。因此，基因组过程必须通过相对快速地改变基因组功能的机制来调节。常规的染色质免疫沉淀（ChIP）实验测量转录因子（TF）的占有率，但对动力学是盲目的，并且不能很好地预测给定基因座的TF功能。为了测量全基因组TF结合动力学，我们用序列特异性S.酿酒酵母转录因子Rap1。Rap1结合动力学和Rap1占有率只有弱相关（R2 = 0.14），但结合动力学更强烈地联系到功能比占用。长Rap1居留耦合到转录激活，而快速结合营业额，我们称之为“研磨”，与低转录输出。因此，通过常规ChIP看起来相同的DNA结合事件可能具有完全不同的潜在相互作用模式，导致相反的功能结果。我们认为TF结合转换是决定转录因子结合功能后果的一个主要调节点，并且在很大程度上是通过控制TF和核小体之间的竞争来介导的。我们的模型（补充图1）预测了一种离合器样机制，该机制快速地将一个转录因子接合到一个稳定的结合状态，反之亦然，以调节TF功能。
Dynamic access to genetic information is central to organismal development and environmental response. Consequently, genomic processes must be regulated by mechanisms that alter genome function relatively rapidly. Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor (TF) occupancy, but are blind to kinetics and are poor predictors of TF function at a given locus. To measure TF binding dynamics genome-wide, we performed competition ChIP with a sequence-specific S. cerevisiae transcription factor, Rap1. Rap1 binding dynamics and Rap1 occupancy were only weakly correlated (R2 = 0.14), but binding dynamics were more strongly linked to function than occupancy. Long Rap1 residence was coupled to transcriptional activation, while fast binding turnover, which we term “treadmilling”, was linked to low transcriptional output. Thus, DNA-binding events that appear identical by conventional ChIP may have starkly different underlying modes of interaction that lead to opposing functional outcomes. We propose that TF binding turnover is a major point of regulation in determining the functional consequences of transcription factor binding, and is mediated in large part by control of competition between TFs and nucleosomes. Our model (Supplementary Fig. 1) predicts a clutch-like mechanism that rapidly engages a treadmilling transcription factor into a stable binding state, or vice-versa, to modulate TF function.
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