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Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer

ABSTRACT: Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer

PROVIDER: PRJNA887022 | ENA |

REPOSITORIES: ENA

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Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (RNA-Seq)

Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (RNA-Seq)

| PRJNA887025 | ENA

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ATAC-Seq)

Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ATAC-Seq)

| PRJNA887027 | ENA

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ChIP-Seq)

Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ChIP-Seq)

| PRJNA887026 | ENA

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (RNA-Seq)

Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.

2023-11-07 | GSE214756 | GEO

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ChIP-Seq)

2023-11-07 | GSE214754 | GEO

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ATAC-Seq)

2023-11-07 | GSE214753 | GEO

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

2016-01-11 | E-GEOD-69043 | biostudies-arrayexpress

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

2016-01-11 | E-GEOD-69044 | biostudies-arrayexpress

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer

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

2023-11-07 | GSE214757 | GEO

Redirecting the pioneering function of FOXA1 with covalent small molecules

Project description:Pioneer transcription factors (TFs) exhibit a special ability to bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report electrophilic small molecules that stereoselectively and site-specifically bind the pioneer TF, FOXA1, at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the covalent ligands relax the canonical DNA binding preference of FOXA1 by strengthening interactions with suboptimal ancillary sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.

2024-09-05 | PXD050685 | Pride

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