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

Author

Listed:
  • Ignacio L. Ibarra

    (European Molecular Biology Laboratory
    Collaboration for Joint PhD Degree between EMBL and Heidelberg University)

  • Nele M. Hollmann

    (European Molecular Biology Laboratory
    Collaboration for Joint PhD Degree between EMBL and Heidelberg University)

  • 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)

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.

Suggested Citation

  • Ignacio L. Ibarra & Nele M. Hollmann & Bernd Klaus & Sandra Augsten & Britta Velten & Janosch Hennig & Judith B. Zaugg, 2020. "Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13888-7
    DOI: 10.1038/s41467-019-13888-7
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    Cited by:

    1. Anna Berenson & Ryan Lane & Luis F. Soto-Ugaldi & Mahir Patel & Cosmin Ciausu & Zhaorong Li & Yilin Chen & Sakshi Shah & Clarissa Santoso & Xing Liu & Kerstin Spirohn & Tong Hao & David E. Hill & Marc, 2023. "Paired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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