Rankin Scott A.

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Scott A.

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  • Article
    Sox17 and ß-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
    (eLife Sciences Publications, 2020-09-07) 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 W. Y. ; Zorn, Aaron M.
    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.