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Functional mapping of androgen receptor enhancer activity [II]

ABSTRACT: In this study we functionally quantified the enhancer activity of all clinical ARBS. We demonstrated that only 7% of ARBS demonstrate androgen-dependent enhancer activation, while 11% have enhancer activity independent of AR binding. Almost all of these AR enhancers have not been previously studied. Surprisingly the vast majority of ARBS (81%) do not have significant enhancer activity. This in vitro annotation strongly correlated to clinical PCa samples. Integrating long-range chromatin interactome and transcriptomic data, we found androgen inducible enhancers were significantly more enriched to serve as anchors for gene looping and acted as a ?hub? to activate AR-regulated genes. To characterize the mechanism of AR enhancers we developed a deep neural network that can successfully predict active enhancers and identify key features for active enhancers. Finally, combining these results with whole genome sequencing of primary and metastatic PCa, we identified and characterized non-coding somatic SNVs that significantly impacted AR enhancer activity of a critical tumour suppressor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154632 | GEO | 2021/03/28

REPOSITORIES: GEO

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Functional mapping of androgen receptor enhancer activity [I]

Project description:In this study we functionally quantified the enhancer activity of all clinical ARBS. We demonstrated that only 7% of ARBS demonstrate androgen-dependent enhancer activation, while 11% have enhancer activity independent of AR binding. Almost all of these AR enhancers have not been previously studied. Surprisingly the vast majority of ARBS (81%) do not have significant enhancer activity. This in vitro annotation strongly correlated to clinical PCa samples. Integrating long-range chromatin interactome and transcriptomic data, we found androgen inducible enhancers were significantly more enriched to serve as anchors for gene looping and acted as a ‘hub’ to activate AR-regulated genes. To characterize the mechanism of AR enhancers we developed a deep neural network that can successfully predict active enhancers and identify key features for active enhancers. Finally, combining these results with whole genome sequencing of primary and metastatic PCa, we identified and characterized non-coding somatic SNVs that significantly impacted AR enhancer activity of a critical tumour suppressor.

2021-03-28 | GSE151064 | GEO

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Project description:Androgen receptor (AR) is typically overexpressed in castration-resistant prostate cancer (CRPC). CRPC-derived VCaP cells display an excessive number of chromatin AR-binding sites (ARBs). This study analyzed direct transcription programs of the AR, the prevalence of AR enhancers and the transcriptional regulators involved in the regulation of at the enhancer regions. The analysis utilized global nuclear run-on sequencing (GRO-seq). The GRO-seq data were integrated with the ARB and VCaP cell-specific transcription factor-binding data. Androgen in 30 min activated and repressed transcription of a large number of genes including novel AR targets IGF-1 receptor and EGF receptor. GRO-seq analysis also revealed that only a fraction of the ARBs resides at functional enhancers. Activation of AR bound enhancers was most potent at the sites that also bound PIAS1, ERG and HDAC3. Our genome-wide data provide new insights how AR can directly control growth-signaling pathways in CPRC cells.

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Prostate Cancer Risk SNPs in Androgen Receptor Target Sites

Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.

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RUNX2 selectively attenuates or augments androgen-driven transcription in prostate cancer

Project description:Prostate carcinogenesis is associated with changes in androgen signaling from driving cellular differentiation to promoting oncogenic behaviors. RUNX2 binds the androgen receptor (AR), and ectopic expression of RUNX2 is linked to prostate cancer (PCa) progression. We therefore investigated genome-wide the influence of RUNX2 on androgen-induced gene expression and AR DNA binding in PCa cells. The predominant function of RUNX2 is to inhibit the androgen response, attributable in part to dissociation of AR from target genes such as the tumor suppressor NKX3-1. At a minority of AR target genes, however, AR activity persists in the presence of RUNX2. Some of these genes are co-operatively stimulated by androgen and RUNX2 signaling and are characterized by the presence of putative enhancers co-occupied by AR and RUNX2. Genes synergistically stimulated by AR and RUNX2 include the invasion-promoting transcription factor SNAI2. Indeed, co-activation of AR and RUNX2, but neither alone, stimulated PCa cell invasiveness, which was abolished by SNAI2 silencing. Accordingly, PCa biopsies most strongly stained for SNAI2 exhibit high nuclear expression of both RUNX2 and AR. The RUNX2-mediated locus-dependent modulation of AR activity in PCa opens a research avenue that may guide the development of novel diagnostic and therapeutic approaches to patient management. total RNA from C4-2B/Rx2dox cells was extracted in biological triplicates from four different conditions. Ethanol vehicle control, dox to induce RUNX2 expression, DHT to activate androgen receptor and DHT+dox combined.

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Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Determine the role of LSD1 in androgen signaling.

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RUNX2 selectively attenuates or augments androgen-driven transcription in prostate cancer

2014-03-20 | GSE52627 | GEO

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2015-07-10 | GSE70679 | GEO

AR ChIP-seq with DHT induction and GSK treatment

Project description:The major pioneer factor activity of FOXA1 in PCa is to facilitate AR recruitment to androgen-regulated enhancers. Therefore, we hypothesized that the decreased FOXA1 binding and enhancer availability by LSD1 inhibition may result in the impairment of subsequent AR recruitment to enhancers. To globally test this hypothesis, we performed AR ChIP-seq in LNCaP cells treated with an LSD1 inhibitors. Consistent with previous reports, DHT treatment can dramatically induce AR binding to chromatin. Significantly, LSD1 inhibitor treatment in presence of DHT stimulation markedly decreased the total number of AR binding peaks and their intensity. We further assessed the impact of LSD1 inhibition on overall AR transcriptional output using RNA-seq data.

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RNA-Seq with DHT induction and/or GSK treatment at 24, 48 hrs and 2 weeks

2019-09-29 | GSE114267 | GEO

Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation [RNA-seq]

Project description:The androgen receptor (AR) antagonist darolutamide has very recently been approved for the treatment of non-metastatic castration resistant prostate cancer (PCa). Here we determined the genome-wide effects of darolutamide on cis-acting regulatory elements involved in androgen signaling with a focus on enhancer and super-enhancer (SE) regions. Darolutamide strongly depleted the AR from regulatory elements and abolished the AR transcriptional signaling. Using two different androgen-dependent PCa cell lines we identified genomic-regions with different affinities for the AR in androgen-stimulated, androgen-depleted and darolutamide-antagonized conditions. Altogether, our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR signaling and AR enhancer activation. Further, we show a dynamic AR cistrome and concomitant adapting chromatin environment to varying conditions and identified regions with high AR affinity in cell lines and tissue samples.

2020-04-10 | GSE148397 | GEO

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