Heterogeneity of transcription factor binding specificity models within and across cell lines.
Heterogeneity of transcription factor binding specificity models within and across cell lines.
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DOI：
10.1101/gr.199166.115
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发表时间：
2016-08
期刊：
影响因子：
7
通讯作者：
Hannenhalli S
中科院分区：
文献类型：
--
作者：
Sharmin M;Bravo HC;Hannenhalli S
复杂的基因表达模式由转录因子（TF）与特定基因组位点的结合介导。TF的体内占有率在很大程度上由TF的DNA结合相互作用伴侣决定，从而激发基于基因组背景的TF占有率模型。然而，迄今为止的方法都假设了一个统一的TF结合模型来解释全基因组细胞类型特异性结合位点。因此，TF占用模型的细胞类型异质性，以及TF占用基础的结合规则在细胞类型间共享的程度尚未研究。在这里，我们开发了一种基于集合的方法（TRISECT）来识别细胞类型特异性TF占用的异构结合规则，并分析这些规则的细胞间类型共享。对23个TF的综合分析表明，通过明确捕获结合规则的异质性，TRISECT可以准确识别体内TF占用率。重要的是，许多来自单个细胞类型的结合规则在不同细胞类型中是共享的，并揭示了不同细胞类型中不同但功能一致的推定靶基因。对预测的细胞类型特异性相互作用伙伴的更仔细检查提供了对TF的上下文特异性功能景观的见解。总之，我们的新的基于整体的方法首次揭示了结合规则的广泛异质性，包括细胞类型内的相互作用伙伴，其中许多超越了细胞类型。值得注意的是，不同细胞类型中共享结合规则的推定目标虽然不同，但表现出显著的功能一致性。
Complex gene expression patterns are mediated by the binding of transcription factors (TFs) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TF's DNA binding interaction partners, motivating genomic context-based models of TF occupancy. However, approaches thus far have assumed a uniform TF binding model to explain genome-wide cell-type–specific binding sites. Therefore, the cell type heterogeneity of TF occupancy models, as well as the extent to which binding rules underlying a TF's occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble-based approach (TRISECT) to identify the heterogeneous binding rules for cell-type–specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-seq data in four to 12 different cell types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy. Importantly, many of the binding rules derived from individual cell types are shared across cell types and reveal distinct yet functionally coherent putative target genes in different cell types. Closer inspection of the predicted cell-type–specific interaction partners provides insights into the context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising the interaction partners within a cell type, many of which nevertheless transcend cell types. Notably, the putative targets of shared binding rules in different cell types, while distinct, exhibit significant functional coherence.