XB-ART-57340Elife January 1, 2020; 9
Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network.
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.
PubMed ID: 32894225
PMC ID: PMC7498262
Article link: Elife
Genes referenced: admp bix1.1 bmp7.1 cdx2 dhh dkk1 eomes ep300 foxa1 foxf1 foxh1 foxi1 foxi2 fst gata3 gata4 gdf3 gjb1 gli1 grhl1 grn gsc hmox1 hnf1b homer1 hoxb3 irx3 isl1 klf5 lhx5 mix1 msx1 nodal nodal1 nodal2 nodal3.1 nodal5 nodal6 nr1h5 osr1 otx1 otx2 pou4f1 rspo2 sfrp2 sia1 six1 smad7 sox17a sox17b.1 szl tfap2a tp63 ventx3.1 wnt11 wnt8a
Antibodies: Sox17a/b Ab2
Morpholinos: ctnnb1 MO1 ctnnb1 MO2 sox17a MO4 sox17a MO5 sox17b.1 MO1 sox17b.1/b.2 MO1
Article Images: [+] show captions
|Figure 5. Sox17 and Bcat epistasis. In situ hybridization of gastrula embryos (dorsal right) injected with sox17-MO or bcat-MO, some of which were co-injected with RNA encoding either mSox17 or a human S37A stabilized Bcat. The genes osr1, six1 and foxa1 are activated by both Sox17 and Bcat, whereas dkk1 and lhx5 are activated by Bcat but repressed by Sox17. Co-injection of mSox17 cannot rescue normal expression in Bcat-MOs, nor can hBcat S37A RNA rescue Sox17-MOs indicating that both Sox17 and Bcat required for normal expression.|
|Figure 7. Model of Sox17 and Bcat coregulation spatial transcription. Differential engagement of Sox17, Bcat and Tcfs on enhancers in different cells modulates spatial expression domains. (A) In ectoderm cells lacking Sox17 (and Nodal signaling), ectoderm-specific gene lhx5 is activated through a Bcat/Tcf dependent mechanism while six1 and dkk1 are not transcribed. (B-C) Sox17 is expressed throughout the endoderm and dorsal mesendoderm, while Bcat activity is the higher in dorsal mesendoderm than deep endoderm. (B) In the dorsal region, Sox17 and Bcat synergistically coactivate six1 in the absence of Tcf, whereas Sox17 exerts a repressive influence on Bcat/Tcf-activation of lhx5 and dkk1. We postulate, however, that in the dorsal region Sox17-mediated repression is insufficient to overcome Bcat/Tcf activation of dkk1. (C) In deep endoderm cells where Bcat activity is lower, Sox17-mediated repression of Bcat/Tcf is sufficient to repress dkk1 and lhx5 transcription, but Bcat activity is not high enough to activate six1.|
References [+] :
Ahmed, Early endodermal expression of the Xenopus Endodermin gene is driven by regulatory sequences containing essential Sox protein-binding elements. 2005, Pubmed, Xenbase