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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development

ABSTRACT: Differentially expressed genes in SOX2 KO vs control forestomach organoids In this dataset, we include expression data from SOX2 KO forestomach organoid and control forestomach organoid

ORGANISM(S): Mus musculus

PROVIDER: GSE297930 | GEO | 2025/06/06

REPOSITORIES: GEO

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [SOX2mousetissue]

Project description:Differentially expressed genes in SOX2 KO vs control forestomachs In this dataset, we include expression data from 4 SOX2 KO forestomachs and 3 control forestomaches

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SOX2 is required for foregut squamous epithelial homeostasis and lost during Barrett’s esophagus development

Project description:Esophageal adenocarcinoma (EA) is increasingly common. EA is thought to arise from a precursor lesion, Barrett’s esophagus (BE), in which chronic bile and acid reflux from the stomach injures the esophagus and induces the esophageal squamous epithelium to transition to a mixed gastric and intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We established a biobank of human patient-derived BE organoids that recapitulated the molecular heterogeneity of BE. Bulk and single-cell transcriptomics, corroborated with analysis of patient tissues, pointed to BE differentiation depending on a balance between two transcription factors that govern foregut versus hindgut embryonic gastrointestinal development: SOX2 (driving esophageal and stomach differentiation) and CDX2 (driving intestinal differentiation). Using squamous-specific inducible Sox2 knockout (Krt5CreER/+; Sox2Δ/Δ;ROSA26LSLTdTomato/+) mice, we found increased basal proliferation and decreased differentiation in the foregut squamous epithelium. Remarkably, Sox2Δ/Δ mice also harbored expanded glands at the squamocolumnar junction, some of which lineage traced to Krt5-expressing cells, indicating metaplasia from squamous epithelium. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated (e.g.,Krt13) and repressed proliferation-associated (e.g., Mki67) targets. Thus, SOX2 is critical for foregut squamous epithelial differentiation and its decreased expression likely an initiating step in progression to BE and thence to EA.

2025-06-07 | PXD063992 | Pride

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [CUT&Run]

Project description:Esophageal adenocarcinoma (EA) is increasingly prevalent and is thought to arise from Barrett’s esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE’s molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2 knockout (Krt5CreER/+; Sox2∆/∆; ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to Krt5-expressing cells. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated (e.g., Krt13) and repressed proliferation-associated (e.g., Mki67) targets. Thus, SOX2 is critical for foregut squamous epithelial differentiation and its decreased expression is likely an initiating step in progression to BE and thence to EA.

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [scRNA-seq]

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [SOX2mousetissue]

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [scRNA-seq]

Project description:SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [scRNA-seq]

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barretts esophagus development [humanBEorganoids]

Project description:Differentially expressed genes in human BE organoids compared to control esophageal squamous organoids.

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barretts esophagus development [humanBEorganoids]

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