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CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276052 | GEO | 2025/02/13

REPOSITORIES: GEO

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CRISPR screening identifies regulators of enhancer-mediated androgen receptor transcription in advanced prostate cancer.

Project description:Amplification of the androgen receptor (AR) locus is the most frequent alteration in metastatic castration-resistant prostate cancer (CRPC). Recently, it was discovered that an enhancer of the AR is co-amplified with the AR gene body and contributes to increased AR transcription and resistance to androgen deprivation therapy. However, the mechanism of enhancer activation in advanced disease is unknown. Here, we used CRISPR-Cas9 screening to identify transcription factors that bind to the AR enhancer and modulate enhancer-mediated AR transcription. We demonstrate that HOXB13, GATA2, and TFAP2C bind the AR enhancer in patient-derived xenografts and directly impact features associated with an active chromatin state. Interestingly, the AR enhancer belongs to a set of regulatory elements that require HOXB13 to maintain FOXA1 binding, further delineating the role of HOXB13 in CRPC. This work provides a framework to functionally identify trans-acting factors required for the activation of disease-related noncoding regulatory elements.

| S-EPMC11867844 | biostudies-literature

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer [ChIP-Seq]

Project description:Amplification of the androgen receptor (AR) locus is the most frequent alteration in metastatic treatment resistant prostate cancer. Recently it was discovered that an enhancer of the AR is co-amplified with the AR gene body and contributes to increased AR transcription and resistance to androgen deprivation therapy. However, the mechanism of enhancer activation in advanced disease is unknown. Here, we used functional genetic screening to identify transcription factors that bind to the AR enhancer and are required for enhancer mediated AR transcription. We validated binding of the transcription factors, HOXB13, GATA2, and TFAP2C in patient derived xenografts and demonstrated differential effects on features associated with active chromatin state including H3K27ac, DNA accessibility, and enhancer-promoter interaction frequency. Interestingly, the AR enhancer belongs to a set of regulatory elements that requires HOXB13 to maintain FOXA1 binding, uncovering a novel role for HOXB13 in castration-resistant prostate cancer. This work provides a framework to functionally identify trans-acting factors required for activation of disease related noncoding regulatory elements.

2025-02-13 | GSE276050 | GEO

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (RNA-Seq)

2025-02-13 | GSE275928 | GEO

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (ATAC-Seq)

2025-02-13 | GSE275927 | GEO

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (4C-Seq)

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CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer

Project description:CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer

| PRJNA1154579 | ENA

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer [ChIP-Seq]

Project description:CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer [ChIP-Seq]

| PRJNA1154584 | ENA

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (RNA-Seq)

Project description:CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (RNA-Seq)

| PRJNA1153598 | ENA

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (ATAC-Seq)

Project description:CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (ATAC-Seq)

| PRJNA1153604 | ENA

CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (4C-Seq)

Project description:CRISPR screening identifies regulators of enhancer mediated androgen receptor transcription in advanced prostate cancer (4C-Seq)

| PRJNA1153602 | ENA

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