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Ibarra, Ignacio L. ; Hollmann, Nele Merret ; Klaus, Bernd ; Augsten, Sandra ; Velten, Britta ; Hennig, Janosch ; Zaugg, Judith B.:
Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions.
In: Nature Communications.
Bd. 11
(2020)
.
- 124.
ISSN 2041-1723
DOI: https://doi.org/10.1038/s41467-019-13888-7
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.