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

Siqian Feng, Chaitanya Rastogi, Ryan Loker, William J. Glassford, H. Tomas Rube, Harmen J. Bussemaker and Richard S. Mann ()
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Siqian Feng: Columbia University
Chaitanya Rastogi: Columbia University
Ryan Loker: Columbia University
William J. Glassford: Columbia University
H. Tomas Rube: Columbia University
Harmen J. Bussemaker: Columbia University
Richard S. Mann: Columbia University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31501-2

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