Chromatin properties of regulatory DNA probed by manipulation of transcription factors
Chromatin properties of regulatory DNA probed by manipulation of transcription factors
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通过操纵转录因子探测调控 DNA 的染色质特性
DOI：
10.1089/cmb.2013.0126
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发表时间：
2014
影响因子：
1.7
通讯作者：
Ko M.S.H.
中科院分区：
文献类型：
--
作者：
Sharov A.A.;Nishiyama A.;Qian Y.;Dudekula D.;Longo D.L.;Schlessinger D.;Ko M.S.H.
转录因子（TF）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，我们搜索的预测功能结合位点进行了系统的计算筛选的各种背景因素（组蛋白修饰，核层蛋白结合，辅因子结合）。我们使用回归分析来测试环境因素是否与在小鼠胚胎干（ES）细胞中诱导或敲低9个TF后相邻基因的上调或下调相关。功能性TF结合位点似乎是活性的（即，被P300、CHD 7、介体、粘着蛋白和SWI/SNF结合）或被抑制（即，具有H3 K27 me 3组蛋白标记并通过Polycomb因子结合）。活性结合位点介导的下调附近的基因敲低激活转录因子或诱导阻遏物。抑制的TF结合位点介导了附近基因的上调（例如，平衡的发育调节剂）。此外，抑制的结合位点介导的抑制作用的TF，通过下调的靶基因后，诱导TF或上调的靶基因后，敲除TF。与DNA结合的转录因子的功能相关的背景因素被用来提高候选转录因子调控的靶基因的鉴定。
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.