SOX17 in cellular reprogramming and cancer

Tan, Daisylyn Senna; Holzner, Markus; Weng, Mingxi; Srivastava, Yogesh; Jauch, Ralf

doi:10.1016/j.semcancer.2019.08.008

Cited by 43 publications

(34 citation statements)

References 119 publications

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“…Many Sox proteins, including Sox17, can bind to recombinant Bcat and Tcfs in vitro and modulate Wnt/Bcat-stimulated transcription of synthetic reporters assays with multimerized Tcf-sites (pTOPFlash) ( Sinner et al, 2007 ; Zorn et al, 1999 ). While a number of models have been proposed to explain how Sox factors might impact Bcat activity, ( Kormish et al, 2010 ; She and Yang, 2015 ; Tan et al, 2019 ), in most cases the in vivo biological relevance of these interactions was unclear. Although the resolution of ChIP-reChIP assays only allow us to demonstrate that Sox17 and Bcat bind chromatin within 150 bp of each other, taken together with published in vitro data, our results suggest that Sox-Bcat or Sox-Bcat-Tcf transcriptional complexes can be assembled on enhancers in vivo.…”

Section: Discussionmentioning

confidence: 99%

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

Mukherjee

Chaturvedi

Rankin

et al. 2020

eLife

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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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Section: Discussionmentioning

confidence: 99%

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

Mukherjee

Chaturvedi

Rankin

et al. 2020

eLife

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“…Many SOX proteins, including Sox17, can bind to recombinant Bcat and Tcfs in vitro and modulate Wnt/Bcat-stimulated transcription of synthetic reporters assays with multimerized Tcf-sites (pTOPFlash) (Sinner et al, 2007;Zorn et al, 1999). While a number of models have been proposed to explain how Sox factors might impact Bcat activity, (Kormish et al, 2010;She and Yang, 2015;Tan et al, 2019), in most cases the in vivo biological relevance of these interactions was unclear. Although the resolution of ChIP-reChIP assays only allow us to demonstrate that Sox17 and Bcat bind chromatin within 150bp of each other, taken together with published in vitro data, our results suggest that Sox-Bcat or Sox-Bcat-Tcf transcriptional complexes can be assembled on enhancers in vivo.…”

Section: Sox-bcat-tcf Interactions On Chromatinmentioning

confidence: 99%

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

Mukherjee

Chaturvedi

Rankin

et al. 2020

Preprint

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Key findings• Sox17 regulates germ layer specification by promoting endoderm differentiation while simultaneously repressing mesectoderm fates.• Functional interactions between Sox17 and Wnt-signaling is a major feature of the GRN controlling endoderm specification and patterning in vivo.• Sox17 and b-catenin co-occupy a subset of enhancers to synergistically stimulate transcription in the absence of Tcfs. • Sox17 regulates the spatial expression domains of Wnt-responsive transcription in the gastrula. ABSTRACT Lineage specification depends on the integration of lineage-determining transcription factors (TFs) and signaling effectors on enhancers to establish gene regulatory networks (GRNs). Sox17 is a key 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. Together, Sox17 and b-catenin bind hundreds of key enhancers. In some cases, Sox17 and b-catenin synergistically activate transcription in the absence of Tcfs, whereas on other enhancers, Sox17 represses ß-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/ß-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and ß-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this could be a general feature of Sox proteins across numerous contexts of development and disease.

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“…Wnt signaling, a cellular pathway pivotal for embryonic development and tissue homeostasis, was found to be effective in primary axis formation, organogenesis, stem cell proliferation, and cell fate decisions as well (35)(36)(37)(38)(39)(40). Its aberrant activation has been associated with the majority of human malignancies, including EC (41,42). In particular, β-catenin is the primary mediator of the oncogenic effect in this signaling pathway (17,21).…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 and β-Catenin as Potential Diagnostic and Prognostic Markers in Endometrial Cancer

Deng

Liang

Han³

2020

Front. Oncol.

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Objectives: Explore the diagnostic and prognostic value of cyclooxygenase-2 and wnt3a/β-catenin pathway in endometrial cancer. Methods: A prospective cohort study of 93 women underwent hysterectomy at the China-Japan Friendship Hospital (61 patients with primary endometrial carcinoma, and 32 control patients with uterine prolapse or leiomyoma of uterus). Cox2 and β-catenin expression were determined by immunohistochemistry. The serum levels of cox2 and wnt3a were detected via ELISA assays. Results: Patients with endometrial cancer showed overexpression of cox2 and β-catenin, as well as significantly higher serum levels of cox2 and wnt3a. The serum cox2 level, which is highly significant in predicting the risk of disease progression (RR, 9.617, 95% confidence interval, 1.162-79.622, P = 0.036), showed good diagnostic and prognostic potential, with cutoff of 55 U/L, but alongside β-catenin expression in tissues, were related to poor prognosis (RR, 12.426; 95% confidence interval, 1.618-95.450; P = 0.015). Conclusion: Serum levels of cox2 and wnt3a exhibited diagnostic value for endometrial cancer. Cox2 serum levels and β-catenin expression also showed potential value of prognostic prediction. Cox2 serum levels might be a potential marker for early diagnosis and prognosis prediction in endometrial cancer.

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SOX17 in cellular reprogramming and cancer

Cited by 43 publications

References 119 publications

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

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

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

Cyclooxygenase-2 and β-Catenin as Potential Diagnostic and Prognostic Markers in Endometrial Cancer

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