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 b-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and b-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses b-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/b-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and b-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.
CITATION STYLE
Mukherjee, S., Chaturvedi, P., Rankin, S. A., Fish, M. B., Wlizla, M., Paraiso, K. D., … Zorn, A. M. (2020). Sox17 and b-catenin co-occupy wntresponsive enhancers to govern the endoderm gene regulatory network. ELife, 9, 1–26. https://doi.org/10.7554/ELIFE.58029
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