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Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors

Author

Listed:
  • Siqian Feng

    (Columbia University
    Columbia University)

  • Chaitanya Rastogi

    (Columbia University)

  • Ryan Loker

    (Columbia University
    Columbia University
    Columbia University
    New York University)

  • William J. Glassford

    (Columbia University
    Columbia University)

  • H. Tomas Rube

    (Columbia University
    University of California)

  • Harmen J. Bussemaker

    (Columbia University
    Columbia University)

  • Richard S. Mann

    (Columbia University
    Columbia University
    Columbia University)

Abstract

In eukaryotes, members of transcription factor families often exhibit similar DNA binding properties in vitro, yet orchestrate paralog-specific gene regulatory networks in vivo. The serially homologous first (T1) and third (T3) thoracic legs of Drosophila, which are specified by the Hox proteins Scr and Ubx, respectively, offer a unique opportunity to address this paradox in vivo. Genome-wide analyses using epitope-tagged alleles of both Hox loci in the T1 and T3 leg imaginal discs, the precursors to the adult legs and ventral body regions, show that ~8% of Hox binding is paralog-specific. Binding specificity is mediated by interactions with distinct cofactors in different domains: the Hox cofactor Exd acts in the proximal domain and is necessary for Scr to bind many of its paralog-specific targets, while in the distal leg domain, the homeodomain protein Distal-less (Dll) enhances Scr binding to a different subset of loci. These findings reveal how Hox paralogs, and perhaps paralogs of other transcription factor families, orchestrate alternative downstream gene regulatory networks with the help of multiple, context-specific cofactors.

Suggested Citation

  • Siqian Feng & Chaitanya Rastogi & Ryan Loker & William J. Glassford & H. Tomas Rube & Harmen J. Bussemaker & Richard S. Mann, 2022. "Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31501-2
    DOI: 10.1038/s41467-022-31501-2
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    1. Pedro B. Pinto & Katrin Domsch & Xuefan Gao & Michaela Wölk & Julie Carnesecchi & Ingrid Lohmann, 2022. "Specificity of the Hox member Deformed is determined by transcription factor levels and binding site affinities," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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