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The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells. [ChIP-Seq]

ABSTRACT: The differentiated functions of the human airway epithelium are coordinated by a complex network of transcription factors. These include the pioneer factors Forkhead box A1 and A2 (FOXA1 and FOXA2), which are well-studied in several tissues, but their role in airway epithelial cells is poorly characterized. Here we define the cistrome of FOXA1 and FOXA2 in primary human bronchial epithelial (HBE) cells by ChIP-seq. Next, siRNA- mediated depletion of each factor is used to investigate their transcriptome by RNA-seq. We found that, as predicted from their DNA-binding motifs, genome-wide occupancy of the two factors showed substantial overlap, however their global impact on gene expression differed. FOXA1 is an abundant transcript in HBE cells, while FOXA2 is expressed at low levels and these factors likely both exhibit auto-regulation and cross-regulation. FOXA1 regulated genes involved in cell adhesion and the maintenance of the epithelial cell identity, particularly through repression of genes associated with epithelial to mesenchymal transition (EMT). FOXA1 also directly targets other transcription factors with a known role in the airway epithelium such as SAM-pointed domain-containing Ets-like factor (SPDEF). The intersection of the cistrome and transcriptome for FOXA1 revealed enrichment of genes involved in epithelial development and tissue morphogenesis. Moreover, depletion of FOXA1 was shown to reduce the transepithelial resistance of HBE cells confirming the role of this factor in maintaining epithelial barrier integrity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143768 | GEO | 2022/01/12

REPOSITORIES: GEO

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The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells. [RNA-seq]

Project description:The differentiated functions of the human airway epithelium are coordinated by a complex network of transcription factors. These include the pioneer factors Forkhead box A1 and A2 (FOXA1 and FOXA2), which are well-studied in several tissues, but their role in airway epithelial cells is poorly characterized. Here we define the cistrome of FOXA1 and FOXA2 in primary human bronchial epithelial (HBE) cells by ChIP-seq. Next, siRNA- mediated depletion of each factor is used to investigate their transcriptome by RNA-seq. We found that, as predicted from their DNA-binding motifs, genome-wide occupancy of the two factors showed substantial overlap, however their global impact on gene expression differed. FOXA1 is an abundant transcript in HBE cells, while FOXA2 is expressed at low levels and these factors likely both exhibit auto-regulation and cross-regulation. FOXA1 regulated genes involved in cell adhesion and the maintenance of the epithelial cell identity, particularly through repression of genes associated with epithelial to mesenchymal transition (EMT). FOXA1 also directly targets other transcription factors with a known role in the airway epithelium such as SAM-pointed domain-containing Ets-like factor (SPDEF). The intersection of the cistrome and transcriptome for FOXA1 revealed enrichment of genes involved in epithelial development and tissue morphogenesis. Moreover, depletion of FOXA1 was shown to reduce the transepithelial resistance of HBE cells confirming the role of this factor in maintaining epithelial barrier integrity.

2022-01-12 | GSE143767 | GEO

Expression data from Spdef +/+ and Spdef -/- mice

Project description:Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef -/- mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef -/- mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef -/- mice identified 43 signficantly upregulated genes and 110 signficantly downregulated genes in the conjunctival epithelium of Spdef -/- mice compared to that of Spdef +/+ control mice (3 fold change, p<0.01). Downregulated genes of particular interested included goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Upregulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and pro-inflammatory genes (Il1-Î±, Il-1Î², Tnf-Î±), all of which are upregulated in dry eye. Interestingly, four Wnt pathway genes were downregulated. Conjunctival epithelium of Spdef +/+ and Spdef -/- mice was collected by laser capture microdissection for RNA extraction and hybridization on Affymetrix microarrays to determine if gene expression patterns in the conjunctival epithelium of Spdef -/- mice is altered compared to that of Spdef +/+ mice.

2013-02-08 | E-GEOD-44101 | biostudies-arrayexpress

Expression data from Spdef +/+ and Spdef -/- mice

Project description:Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef -/- mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef -/- mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef -/- mice identified 43 signficantly upregulated genes and 110 signficantly downregulated genes in the conjunctival epithelium of Spdef -/- mice compared to that of Spdef +/+ control mice (3 fold change, p<0.01). Downregulated genes of particular interested included goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Upregulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and pro-inflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are upregulated in dry eye. Interestingly, four Wnt pathway genes were downregulated.

2013-02-08 | GSE44101 | GEO

Ets homologous factor has critical roles in epithelial dysfunction in airway disease [RNA-seq]

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2022-10-31 | GSE191182 | GEO

Transcriptome of Foxa1/Foxa2-deficient colon [RNA]

Project description:FOXA1 and FOXA2 are essentail transcription factors for proper gut development. In adults, they have a role in the differentiation of intestinal secretory cell lineages and were also reporeted to directly activate Muc2 transcription. Here we show that deletion of Foxa1 and Foxa2 in mouse intestinal epithelium leads to a downregulation of glycosylation genes in the colon and to a massive change of the colonic surface glycans. In turn, the microbiome composition shifts dramatically and spontaneous inflammatory bowel disease ensued. We conclude that vertebrates shape a favorable microbiome by establishing a glycocalyx to nurture specific bacterial taxa through control of the epithelial glycosylation program by the FoxA transcription factors.

2024-05-14 | GSE263630 | GEO

FOXA2 regulates a network of genes involved in critical functions of intestinal epithelia

Project description:Background and Aims: The forkhead box A (FOXA) family of pioneer transcription factors is critical for the development of many endoderm-derived tissues including the lung and the liver. Here we investigate the role of FOXA2 in regulating intestinal epithelial cell function. Methods: ChIP-seq was used to identify FOXA2 binding sites genome-wide. Targets of FOXA2 were validated using ChIP-qPCR and siRNA-mediated depletion of FOXA1/2 followed by RT-qPCR. A luciferase-based assay was used to measure intracellular cAMP after FOXA1/2 modulation.Results: Peaks of FOXA2 occupancy were frequent at loci contributing to gene ontology pathways of regulation of cell migration, cell motion, and plasma membrane function. Depletion of both FOXA1 and FOXA2 led to a significant reduction in the expression of multiple transmembrane proteins including ion transporters. One of the targets was the adenosine A2B receptor, and reduced receptor mRNA levels were associated with a functional decrease in intracellular cAMP. We also observed that 30% of FOXA2 binding sites contained a GATA motif and that FOXA1/A2 depletion reduced GATA-4, but not GATA-6 protein levels. Conclusions: These data show that FOXA2 plays a critical role in regulating intestinal epithelial cell function. FOXA2 depletion affects the expression of ion transporters and other transmembrane proteins, which form a network essential for maintaining normal ion and solute transport. Moreover, we show that the FOXA and GATA families of transcription factors may work cooperatively to regulate gene expression genome-wide. To determine the role of FOXA2 in regulating gene expression in intestinal epithelial cells, ChIP-seq was performed for FOXA2 in Caco2 (colorectal adenocarcinoma) cells.

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Ets homologous factor has critical roles in epithelial dysfunction in airway disease [ChIP-seq]

Project description:Ets homologous factor (EHF) is an Ets family transcription factor expressed in many epithelial cell types including those lining the respiratory system. Disruption of the airway epithelium is central to many lung diseases, and a network of transcription factors coordinates its normal function. EHF can act as a transcriptional activator or a repressor. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), showed that EHF binding sites in lung epithelial cells are enriched at promoters and coincide with putative enhancers, marked by specific histone modifications. Using EHF ChIP-seq and RNA-seq after EHF depletion, we show its targets in HBE cells are enriched for genes involved in degradation of misfolded proteins, inflammation, and wound repair.

2017-05-22 | GSE85401 | GEO

single nuclei transcriptomics of colonic epithelium

Project description:FOXA1 and FOXA2 are essentail transcription factors for proper gut development. In adults, they play a role in the differentiation of intestinal secretory cells and were also reporeted to directly activate Muc2 transcription. Here we show that deletion of Foxa1 and Foxa2 in mouse intestinal epithelium leads to a downregulation of glycosylation genes in the colon and to a massive change of the colonic surface glycans, which in turn leads to dysbiosis and to inflammatory bowel disease. In order to associate this phenotype with a specific colonic lineage, we generated cell specific gene sets by performing single nuclei RNA-seq on colonic tissue from control mice. Gene set enrichment analysis demonstrated major changes in Goblet cell genes following Foxa1/2 deletion, including glycosylation genes. However, other lineages were also affected. We concluded that vertebrates shape a favorable microbiome by establishing a glycocalyx to nurture specific bacterial taxa through control of the epithelial glycosylation program by the FoxA transcription factors.

2024-05-14 | GSE263631 | GEO

FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity

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