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

Siqian FengChaitanya RastogiRyan LokerWilliam J GlassfordH Tomas RubeHarmen J BussemakerRichard S Mann
Published in: Nature communications (2022)
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.
Keyphrases
  • transcription factor
  • dna binding
  • genome wide
  • dna methylation
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  • gene expression
  • dna damage
  • dna repair
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