Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
| Autor: | Aaron M. Zorn, Marcin Wlizla, Ken W.Y. Cho, Ira L. Blitz, Matthew T. Weirauch, Melissa MacDonald, Praneet Chaturvedi, Kitt D. Paraiso, Scott A. Rankin, Shreyasi Mukherjee, Margaret B. Fish, Xiaoting Chen |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Xenopus Gene regulatory network 0302 clinical medicine Stem Cell Research - Nonembryonic - Human Transcriptional regulation SOXF Transcription Factors Gene Regulatory Networks Biology (General) Wnt Signaling Pathway beta Catenin biology General Neuroscience Endoderm Wnt signaling pathway General Medicine Cell biology sox17 medicine.anatomical_structure embryonic structures Medicine transcription Research Article Biotechnology Beta-catenin animal structures QH301-705.5 Science 1.1 Normal biological development and functioning General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Wnt developmental biology Underpinning research medicine Genetics Animals Enhancer Transcription factor General Immunology and Microbiology Human Genome beta-catenin Gastrula Stem Cell Research Wnt Proteins 030104 developmental biology biology.protein enhancers Biochemistry and Cell Biology 030217 neurology & neurosurgery Developmental Biology Definitive endoderm |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| Popis: | 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 inXenopusgastrulae. 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. |
| Databáze: | OpenAIRE |
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