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The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during positive selection in the thymus

ABSTRACT: The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during positive selection in the thymus

PROVIDER: PRJNA717182 | ENA |

REPOSITORIES: ENA

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The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during positive selection in the thymus

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

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.

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Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [ChIP-Seq]

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

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Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [gene expression]

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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.

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Regulatory cistrome landscape of Foxa1 and Foxa2 during prostate cancer progression [ChIP-seq]

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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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Foxa1 and Foxa2 are Required for Sexual Dimorphism in Liver Cancer - Gene Expression

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

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Gene expression profiles of Foxa1 and Foxa2 single and double mutants in embryonic mouse liver

Project description:Gene expression of Foxa1 and Foxa2 single and double mutant livers (embryonic day 18.5)

2012-06-22 | E-MEXP-3428 | biostudies-arrayexpress

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