Specificity landscapes unmask submaximal binding site preferences of transcription factors
Specificity landscapes unmask submaximal binding site preferences of transcription factors
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DOI：
10.1073/pnas.1811431115
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发表时间：
2018-11-06
影响因子：
11.1
通讯作者：
Ansari, Aseem Z.
中科院分区：
文献类型：
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作者：
Bhimsaria, Devesh;Rodriguez-Martinez, Jose A.;Ansari, Aseem Z.
我们开发了差异特异性和能量景观（DiSEL）分析，以全面比较通过高通量实验平台和尖端计算方法获得的DNA-蛋白质相互作用组（DPI）。虽然大多数方法都能识别出高亲和力的DNA结合位点，但DiSEL发现了同源转录因子所显示的细微差别的序列偏好。726 DPI的成对分析揭示了在中等至低亲和力结合位点（次最大位点）的同源特异性差异。对41种转录因子变体的DiSEL分析显示，许多致病突变导致结合位点偏好的等位基因特异性变化。我们专注于一组高度同源的因子，它们具有不同的生物学作用，但使用相同的氨基酸侧链“阅读”DNA。而不是直接读出，我们的研究结果表明，DNA非接触侧链变构有助于塑造不同的序列偏好密切相关的转录因子家族的成员。
We have developed Differential Specificity and Energy Landscape (DiSEL) analysis to comprehensively compare DNA-protein interactomes (DPIs) obtained by high-throughput experimental platforms and cutting edge computational methods. While high-affinity DNA binding sites are identified by most methods, DiSEL uncovered nuanced sequence preferences displayed by homologous transcription factors. Pairwise analysis of 726 DPIs uncovered homolog-specific differences at moderate-to low-affinity binding sites (submaximal sites). DiSEL analysis of variants of 41 transcription factors revealed that many disease-causing mutations result in allele-specific changes in binding site preferences. We focused on a set of highly homologous factors that have different biological roles but "read" DNA using identical amino acid side chains. Rather than direct readout, our results indicate that DNA noncontacting side chains allosterically contribute to sculpt distinct sequence preferences among closely related members of transcription factor families.