ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors.
ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors.
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DOI：
10.1101/gr.185157.114
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发表时间：
2015-06
期刊：
影响因子：
7
通讯作者：
Meijsing SH
中科院分区：
文献类型：
--
作者：
Starick SR;Ibn-Salem J;Jurk M;Hernandez C;Love MI;Chung HR;Vingron M;Thomas-Chollier M;Meijsing SH
糖皮质激素受体（GR）的经典DNA识别序列似乎只存在于一小部分结合的基因组区域。为了鉴定负责将这种转录因子（TF）募集到单个基因座的序列，我们转向高分辨率ChIP-exo方法。我们利用这个信号，通过使用ExoProfiler（一种基于DNA结合基序的计算管道）以单碱基对分辨率确定TF结合的足迹分布。当应用于我们的GR和少数可用的公共ChIP-exo数据集时，我们发现ChIP-exo足迹是基因组TF关联的蛋白质和识别序列特异性签名。此外，我们表明，ChIP-exo捕获信息的TF以外的一个直接靶向的抗体在ChIP程序。因此，ChIP-exo足迹的形状可用于区分直接和间接（与其他DNA结合的蛋白质的束缚）GR的DNA缔合。总之，我们的研究结果表明，经典识别序列的缺乏可以通过直接GR与比先前已知的更广谱的序列结合来解释，作为同二聚体或作为异二聚体与TF的ETS或TEAD家族的成员结合在一起，或者通过FOX或STAT蛋白间接募集。ChIP-exo足迹还带来了结构上的见解，并定位了与所研究的TF的晶体结构相容的DNA：蛋白质交联点。总的来说，我们普遍适用的足迹为基础的方法揭示了新的结构和功能的见解，基因组合作和协会的TF的不同方式。
The classical DNA recognition sequence of the glucocorticoid receptor (GR) appears to be present at only a fraction of bound genomic regions. To identify sequences responsible for recruitment of this transcription factor (TF) to individual loci, we turned to the high-resolution ChIP-exo approach. We exploited this signal by determining footprint profiles of TF binding at single-base-pair resolution using ExoProfiler, a computational pipeline based on DNA binding motifs. When applied to our GR and the few available public ChIP-exo data sets, we find that ChIP-exo footprints are protein- and recognition sequence-specific signatures of genomic TF association. Furthermore, we show that ChIP-exo captures information about TFs other than the one directly targeted by the antibody in the ChIP procedure. Consequently, the shape of the ChIP-exo footprint can be used to discriminate between direct and indirect (tethering to other DNA-bound proteins) DNA association of GR. Together, our findings indicate that the absence of classical recognition sequences can be explained by direct GR binding to a broader spectrum of sequences than previously known, either as a homodimer or as a heterodimer binding together with a member of the ETS or TEAD families of TFs, or alternatively by indirect recruitment via FOX or STAT proteins. ChIP-exo footprints also bring structural insights and locate DNA:protein cross-link points that are compatible with crystal structures of the studied TFs. Overall, our generically applicable footprint-based approach uncovers new structural and functional insights into the diverse ways of genomic cooperation and association of TFs.
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