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Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network.

  • Author(s): Mukherjee, Shreyasi
  • Chaturvedi, Praneet
  • Rankin, Scott A
  • Fish, Margaret B
  • Wlizla, Marcin
  • Paraiso, Kitt D
  • MacDonald, Melissa
  • Chen, Xiaoting
  • Weirauch, Matthew T
  • Blitz, Ira L
  • Cho, Ken Wy
  • Zorn, Aaron M
  • et al.
Abstract

Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.

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