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

Ignacio L. Ibarra, Nele M. Hollmann, Bernd Klaus, Sandra Augsten, Britta Velten, Janosch Hennig and Judith B. Zaugg ()
Additional contact information
Ignacio L. Ibarra: European Molecular Biology Laboratory
Nele M. Hollmann: European Molecular Biology Laboratory
Bernd Klaus: European Molecular Biology Laboratory
Sandra Augsten: European Molecular Biology Laboratory
Britta Velten: European Molecular Biology Laboratory
Janosch Hennig: European Molecular Biology Laboratory
Judith B. Zaugg: European Molecular Biology Laboratory

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-13888-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13888-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-13888-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().