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

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ID: 78979
2020
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Abstract
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.
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ibarra2020mechanisticnature Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ibarra, Ignacio L;Hollmann, Nele M;Klaus, Bernd;Augsten, Sandra;Velten, Britta;Hennig, Janosch;Zaugg, Judith B;
Journal Nature communications
Year 2020
DOI
10.1038/s41467-019-13888-7
URL
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