Sharov Alexei A, Nishiyama Akira, Qian Yong, Dudekula Dawood B, Longo Dan L, Schlessinger David, Ko Minoru S H
1 National Institute on Aging, National Institutes of Health , Baltimore, Maryland.
J Comput Biol. 2014 Aug;21(8):569-77. doi: 10.1089/cmb.2013.0126. Epub 2014 Jun 11.
Transcription factors (TFs) bind to DNA and regulate the transcription of nearby genes. However, only a small fraction of TF binding sites have such regulatory effects. Here we search for the predictors of functional binding sites by carrying out a systematic computational screening of a variety of contextual factors (histone modifications, nuclear lamin-bindings, and cofactor bindings). We used regression analysis to test if contextual factors are associated with upregulation or downregulation of neighboring genes following the induction or knockdown of the 9 TFs in mouse embryonic stem (ES) cells. Functional TF binding sites appeared to be either active (i.e., bound by P300, CHD7, mediator, cohesin, and SWI/SNF) or repressed (i.e., with H3K27me3 histone marks and bound by Polycomb factors). Active binding sites mediated the downregulation of nearby genes upon knocking down the activating TFs or inducing repressors. Repressed TF binding sites mediated the upregulation of nearby genes (e.g., poised developmental regulators) upon inducing TFs. In addition, repressed binding sites mediated repressive effects of TFs, identified by the downregulation of target genes after the induction of TFs or by the upregulation of target genes after the knockdown of TFs. The contextual factors associated with functions of DNA-bound TFs were used to improve the identification of candidate target genes regulated by TFs.
转录因子（TFs）与DNA结合并调节附近基因的转录。然而，只有一小部分TF结合位点具有这种调节作用。在这里，我们通过对多种上下文因素（组蛋白修饰、核纤层结合和辅因子结合）进行系统的计算筛选，寻找功能性结合位点的预测因子。我们使用回归分析来测试在小鼠胚胎干细胞（ES细胞）中诱导或敲低9种TF后，上下文因素是否与邻近基因的上调或下调相关。功能性TF结合位点似乎要么是活跃的（即被P300、CHD7、中介体、黏连蛋白和SWI/SNF结合），要么是受抑制的（即带有H3K27me3组蛋白标记并被多梳因子结合）。在敲低激活型TF或诱导抑制因子时，活跃结合位点介导附近基因的下调。在诱导TF时，受抑制的TF结合位点介导附近基因（如处于待命状态的发育调节因子）的上调。此外，受抑制的结合位点介导TF的抑制作用，这可通过诱导TF后靶基因的下调或敲低TF后靶基因的上调来确定。与DNA结合的TF功能相关的上下文因素被用于改进对TF调控的候选靶基因的识别。
