Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions.,Nature Communications

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Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-08 , DOI: 10.1038/s41467-019-13888-7
Ignacio L Ibarra _{1,

2} , Nele M Hollmann _{1,

2} , Bernd Klaus ₃ , Sandra Augsten ₁ , Britta Velten ₃ , Janosch Hennig ₁ , Judith B Zaugg ₁

Affiliation

Recent high-throughput transcription factor (TF) binding assays revealed that TF cooperativity is a widespread phenomenon. However, a global mechanistic and functional understanding of TF cooperativity is still lacking. To address this, here we introduce a statistical learning framework that provides structural insight into TF cooperativity and its functional consequences based on next generation sequencing data. We identify DNA shape as driver for cooperativity, with a particularly strong effect for Forkhead-Ets pairs. Follow-up experiments reveal a local shape preference at the Ets-DNA-Forkhead interface and decreased cooperativity upon loss of the interaction. Additionally, we discover many functional associations for cooperatively bound TFs. Examination of the link between FOXO1:ETV6 and lymphomas reveals that their joint expression levels improve patient clinical outcome stratification. Altogether, our results demonstrate that inter-family cooperative TF binding is driven by position-specific DNA readout mechanisms, which provides an additional regulatory layer for downstream biological functions.

中文翻译：

深入了解转录因子的协同作用及其对蛋白质表型相互作用的影响。

最近的高通量转录因子（TF）结合测定表明TF合作性是一种普遍现象。但是，仍然缺乏对TF合作性的全局机制和功能性理解。为了解决这个问题，我们在这里介绍了一个统计学习框架，该框架基于下一代测序数据提供了对TF合作性及其功能后果的结构性见解。我们确定DNA形状是协同作用的驱动力，对Forkhead-Ets对具有特别强的作用。后续实验揭示了Ets-DNA-Forkhead界面处的局部形状偏好，并在失去相互作用后降低了协同作用。此外，我们发现了许多绑定绑定的TF的功能关联。检查FOXO1之间的链接：ETV6和淋巴瘤表明它们的联合表达水平改善了患者的临床结局分层。总之，我们的结果表明，家族间合作TF结合是由位置特异性DNA读出机制驱动的，该机制为下游生物学功能提供了额外的调控层。

更新日期：2020-01-08

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