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The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells.

ABSTRACT: The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells.

PROVIDER: PRJNA601638 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10902582.fastq.gz	Fastqsanger.gz
	SRR10902583.fastq.gz	Fastqsanger.gz
	SRR10902584.fastq.gz	Fastqsanger.gz
	SRR10902585.fastq.gz	Fastqsanger.gz
	SRR10902586.fastq.gz	Fastqsanger.gz

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

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

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

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

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The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells. [ChIP-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 | GSE143768 | GEO

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

2022-01-12 | GSE143767 | GEO

The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells.

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 chromatin immunoprecipitation with deep-sequencing (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 both these factors likely exhibit autoregulation and cross-regulation. FOXA1 regulated loci are involved in cell adhesion and the maintenance of 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.

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The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-01-12 | GSE143769 | GEO

Staufen1 Represses the FOXA1-Regulated Transcriptome by Destabilizing FOXA1 mRNA in Colorectal Cancer Cells

Project description:Transcription factors play key roles in development and diseases by controlling gene expression. Forkhead Box A1 (FOXA1) is a pioneer transcription factor essential for mouse development that plays important roles in prostate and breast cancer. In colorectal cancer (CRC), we have found that FOXA1 is significantly downregulated, suggesting potential tumor suppressive functions. However, the mechanism(s) by which FOXA1 is downregulated in CRC cells remain largely unclear. We investigated the regulation of FOXA1 expression in CRC, focusing on well-differentiated CRC cells where it is robustly expressed. Genome-wide stability assays identified FOXA1 as an unstable mRNA in CRC cells. We validated FOXA1 mRNA instability in multiple CRC lines and patient-derived CRC organoids and found FOXA1 mRNA is degraded via its 3’UTR. Through FOXA1 3’UTR RNA pulldowns, we identified Staufen1 (STAU1) as a potential regulator of FOXA1. Indeed, knockdown of STAU1 results in increased expression of FOXA1 mRNA and protein due to increased FOXA1 mRNA stability. A subset of the STAU1-regulated transcriptome is enriched for FOXA1 targets, whose expression also increases upon STAU1 knockdown. Collectively, this study uncovers the molecular mechanism by which FOXA1 is regulated in CRC and provides insights into our understanding of the complex mechanisms of gene regulation in cancer.

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Nucleation of DNA Repair Factors by FOXA1 Links DNA Demethylation and Transcriptional Pioneering

Project description:We report that the winged helix transcription factor FOXA1 is unexpectedly associated with components of single and double stranded-DNA repair complexes. Biochemical studies and high-throughput approaches validated the hierarchical composition of this FOXA1-nucleated machinery and revealed the dependency on FOXA1 for global targeting of the key repair polymerase POLB. Genome-wide DNA methylomes at single-base resolution demonstrated that FOXA1-DNA repair complex is functionally linked to DNA demethylation in a lineage specific fashion. Loss-of-function studies indicate that a significant portion of FOXA1-bound regions display localized reestablishment of methylation and that the subsets with most consistent hypermethylation are represented by active promoters and enhancers that also exhibit the greatest depletion of POLB following FOXA1 removal. Consistently, forced expression of FOXA1 commits its binding sites to an active DNA demethylation in a POLB dependent manner. Finally, we showed that FOXA1-associated DNA demethylation is tightly coupled with genomic targeting of estrogen receptor and estrogen responsiveness. Together, our results link FOXA1-associated DNA demethylation to its transcriptional pioneering.

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