The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during positive selection in the thymus
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ABSTRACT:
PROVIDER: PRJNA717182 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14067743_1.fastq.gz | Fastqsanger.gz | |||
| SRR14067743_2.fastq.gz | Fastqsanger.gz | |||
| SRR14067744_1.fastq.gz | Fastqsanger.gz | |||
| SRR14067744_2.fastq.gz | Fastqsanger.gz | |||
| SRR14067745_1.fastq.gz | Fastqsanger.gz |
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Project description:Here we show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection at the transition from CD4+CD8+ double positive (DP) to single positive (SP thymocyte). Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes led to a partial arrest at the transition from DP to SP, with a reduction in the number of cells undergoing positive selection, and reduced the number and maturation of both CD4SP and CD8SP populations, with a reduction in peripheral naïve CD4+ T-cells. Foxa1 and Foxa2 were required for physiological levels of expression of several genes which encoding splicing factors (Mbnl1, Sf3b1, Hnrnpa1) in cells undergoing positive selection. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated leading to more than 859 significantly differentially expressed exons compared to control, with many genes important for T cell development and for RNA splicing showing differentially used exons.
2021-07-13 | GSE169602 | GEO
Project description:During positive selection at the transition from CD4+CD8+ double-positive (DP) to single-positive (SP) thymocyte, TCR signalling results in appropriate MHC restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection of mouse T cells and that Foxa1 and Foxa2 have overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+ T cells. Foxa1 and Foxa2 regulated the expression of many genes encoding splicing factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prpf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons. Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple differentially used exons. Thus, Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and, by also regulating splicing of splicing factors, they exert widespread control of alternative splicing.
| S-EPMC8353164 | biostudies-literature
Project description:Activation of the androgen receptor (AR) is the key lineage-specific oncogenic pathway and the primary therapeutic target in prostate cancer. While AR signaling is enabled by the pioneer transcription factor FOXA1, its homologue FOXA2 is specifically expressed in advanced lineage plasticity prostate cancers that have lost the AR signaling axis. However, their roles and utility as a drug target remain incompletely characterized. Here, we show an unexpected collaboration of FOXA1 and FOXA2 in mediating AR-independent cell proliferation in different lineage plasticity cancer subtypes. Conversely, joint loss-of-function or pharmacologic disruption of FOXA1 and FOXA2 leads to the collapse of lineage-specific oncogenic transcription factors followed by cell cycle arrest. In summary, our findings uncover a druggable dependency for AR-positive and -negative prostate cancers.
2025-08-30 | GSE279872 | GEO
Project description:Activation of the androgen receptor (AR) is the key lineage-specific oncogenic pathway and the primary therapeutic target in prostate cancer. While AR signaling is enabled by the pioneer transcription factor FOXA1, its homologue FOXA2 is specifically expressed in advanced lineage plasticity prostate cancers that have lost the AR signaling axis. However, their roles and utility as a drug target remain incompletely characterized. Here, we show an unexpected collaboration of FOXA1 and FOXA2 in mediating AR-independent cell proliferation in different lineage plasticity cancer subtypes. Conversely, joint loss-of-function or pharmacologic disruption of FOXA1 and FOXA2 leads to the collapse of lineage-specific oncogenic transcription factors followed by cell cycle arrest. In summary, our findings uncover a druggable dependency for AR-positive and -negative prostate cancers.
2025-08-30 | GSE281784 | GEO
Project description:AR is tightly regulated by many transcriptional cofactors, including key pioneer factor such as FOXA1 and GATA2. While FOXA1 was recently shown to be able to redistribute AR across the genome, how GATA2 regulates AR cistrome has not been carefully investigated. Here, we report that, unlike FOXA1, GATA2 is unable to reprogram AR, but instead it enhances AR program by inducing AR expression and augmenting AR co-occupancy, thereby acting as a pure AR coactivator, rather than a pioneer factor. On the other hand, AR co-occupancy enhances both GATA2 and FOXA1 binding on the chromatin, forming a positive feedback loop. Importantly, we found that FOXA1 is also capable of reprogramming GATA2 by recruiting GATA2 from GATA motif to FKHD-containing regions, being analogous to its pioneering effect on AR signaling. By contrast, GATA2 simply acts as a co-activator of FOXA1 with a lack of pioneering ability. ChIP_Seq examination of AR, FoxA1 and GATA2 binding sites in LNCaP and DU145 cells
2016-01-11 | E-GEOD-69043 | biostudies-arrayexpress
Project description:AR is tightly regulated by many transcriptional cofactors, including key pioneer factor such as FOXA1 and GATA2. While FOXA1 was recently shown to be able to redistribute AR across the genome, how GATA2 regulates AR cistrome has not been carefully investigated. Here, we report that, unlike FOXA1, GATA2 is unable to reprogram AR, but instead it enhances AR program by inducing AR expression and augmenting AR co-occupancy, thereby acting as a pure AR coactivator, rather than a pioneer factor. On the other hand, AR co-occupancy enhances both GATA2 and FOXA1 binding on the chromatin, forming a positive feedback loop. Importantly, we found that FOXA1 is also capable of reprogramming GATA2 by recruiting GATA2 from GATA motif to FKHD-containing regions, being analogous to its pioneering effect on AR signaling. By contrast, GATA2 simply acts as a co-activator of FOXA1 with a lack of pioneering ability. genetic_modification_design
2016-01-11 | E-GEOD-69044 | biostudies-arrayexpress
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
Project description:To characterize the genome-wide regulatory cistrome of Foxa1 and Foxa2, we performed both Foxa1 and Foxa2 chromatin immunoprecipitation followed by sequencing (ChIP-seq) on freshly dissociated prostate tumor cells at the early stage (2 weeks post tamoxifen administration) and the late stage (6 months post tamoxifen administration) of NEPC progression, respectively.
2022-10-31 | GSE191182 | GEO
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.
2015-08-06 | E-GEOD-66218 | biostudies-arrayexpress
Project description:Gene expression changes between livers of treated WT and dKO (Foxa1 and Foxa2 KO) male and female mice and untreated female (WT and dKO) mice were measured to identify pathways related to Foxa1/2 regulation of pathways involved in liver cancer. The experiment uses 4 replicates each for 6 conditions
2012-01-20 | E-GEOD-32244 | biostudies-arrayexpress