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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69044 | GEO | 2016/01/11

SECONDARY ACCESSION(S): PRJNA284391

REPOSITORIES: GEO

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

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

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

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

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

2016-01-11 | GSE69043 | GEO

The role of the transcription factors GATA2 and FOXA1 in immortalized basal-like prostate epithelial cells

Project description:GATA2 and FOXA1 are pioneering factors for Androgen Receptor (AR) in prostate cancer cells. Less is known about their role in benign epithelial prostate cells. We investigated if they had the ability to induce differentiation in an undifferentiated prostatic context. Benign basal-like prostate epithelial cells 957E/hTERT-AR cells (a gift from John T. Isaacs lab, Johns Hopkins, MD, USA) were transduced with LentiORF RFP control lentiviral particles. The 957E/hTERT-AR-RFP cells were then transduced with GATA2 and FOXA1 lentiviral particles, and we called the new cell lines hTERT/AR-GATA2 and hTERT/AR-FOXA1, respectively. hTERT/AR-GATA2 is a stable selected cell line and treated with 1 nM anabolic steroids, R1881, or ethanol (ET-OH) for 48 hrs. 957E/hTERT/AR-FOXA1 is a transient cell line, because FOXA1 protein is quickly lost. Twenty four hours post transduction with FOXA1 lentivral particles, 1 nM androgen R1881 or ethanol (ET-OH) were added at time for medium exchange and further treated for 24 hours. GATA-2 and FOXA1 ability to induce differentiation was assessed.

2018-12-01 | E-MTAB-5121 | biostudies-arrayexpress

Altered chromatin remodeling by FOXA1 mutations promotes androgen independence and prostate cancer aggressiveness [ChIP-seq]

Project description:FKHD-mutant (FKHDm) FOXA1 has impaired ability to bind chromatin and thus failed to rescue wildtype FOXA1-mediated transcriptional program. FKHDm FOXA1 formed much stronger interaction with the AR protein, thereby preventing AR from binding to the chromatin.

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Altered chromatin remodeling by FOXA1 mutations promotes androgen independence and prostate cancer aggressiveness [gene expression]

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H3K27ac ChIP-seq in LNCaP cell line overexpressing WT or mutant FOXA1

Project description:Our data suggested that FKHD-MSs impair the chromatin binding of FOXA1 to AR-dependent enhancers and thus suppress AR transcriptional activity, and promote PCa progression through increasing FOXA1 binding to a subset of AR-independent enhancers that regulates transcription of genes mediating EMT and metastasis

2019-10-15 | GSE133387 | GEO

FOXA1 ChIP-seq in LNCaP cell line overexpressing WT or mutant FOXA1

2019-10-15 | GSE133386 | GEO

RNA-seq in LNCaP cell line overexpressing WT or mutant FOXA1

2019-10-15 | GSE133384 | 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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