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

• Published in: Nature communications Vol. 11; no. 1; p. 124
• Main Authors: Ibarra, Ignacio L., Hollmann, Nele M., Klaus, Bernd, Augsten, Sandra, Velten, Britta, Hennig, Janosch, Zaugg, Judith B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/47; 631/114/2415; 631/208/200; 631/337/572; 631/337/572/2102; 631/535/878; Binding; Biophysical Phenomena; Cooperativity; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; DNA - metabolism; DNA sequencing; ETS protein; Forkhead protein; FOXO1 protein; Gene Expression Regulation; Humanities and Social Sciences; Humans; Kinetics; Learning; Lymphoma; Models, Genetic; multidisciplinary; Next-generation sequencing; Phenotype; Phenotypes; Protein Binding; Proteins; Science; Science (multidisciplinary); Statistics; Transcription factors; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13888-7

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. Although transcription factor (TF) cooperativity is widespread, a global mechanistic understanding of the role of TF cooperativity is still lacking. Here the authors introduce a statistical learning framework that provides structural insight into TF cooperativity and its functional consequences based on next generation sequencing data and provide mechanistic insights into TF cooperativity and its impact on protein-phenotype interactions.