Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [GRO-Seq]

ABSTRACT: Transcription factors (TFs) activate enhancers to drive cell-specific gene expression in response to signals, but our understanding of enhancer assembly in signaling events is incomplete. Here we show that Androgen Receptor (AR), a steroid hormone signaling-regulated transcription factor, forms phase-separated condensates in response to androgen to activate enhancers. We demonstrate that the intrinsically disordered NTD of AR drives condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by some IDRs from other proteins for AR condensation capacity and transactivation function. Extending the polyQ tract within AR NTD strengthens AR phase separation and also leads to impaired transcriptional activity. PolyQ expansion does not affect AR binding on enhancers, but instead impairs enhancer assembly. These results suggest that AR phase separation mediates enhancer assembly, and an optimal level of AR condensation is required for its proper function in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate transcription in response to signals. Our study supports that alteration of the fine-tuned protein condensation might underlie AR-related human pathologies, therefore providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR condensation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215162 | GEO | 2023/10/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [ChIP-Seq]

Project description:Transcription factors (TFs) activate enhancers to drive cell-specific gene expression in response to signals, but our understanding of enhancer assembly in signaling events is incomplete. Here we show that Androgen Receptor (AR), a steroid hormone signaling-regulated transcription factor, forms phase-separated condensates in response to androgen to activate enhancers. We demonstrate that the intrinsically disordered NTD of AR drives condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by some IDRs from other proteins for AR condensation capacity and transactivation function. Extending the polyQ tract within AR NTD strengthens AR phase separation and also leads to impaired transcriptional activity. PolyQ expansion does not affect AR binding on enhancers, but instead impairs enhancer assembly. These results suggest that AR phase separation mediates enhancer assembly, and an optimal level of AR condensation is required for its proper function in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate transcription in response to signals. Our study supports that alteration of the fine-tuned protein condensation might underlie AR-related human pathologies, therefore providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR condensation.

2023-10-31 | GSE215161 | GEO

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

2023-10-31 | GSE215160 | GEO

Targeting the N-terminus of the androgen receptor for prostate cancer therapy

Project description:All current clinically approved androgen deprivation therapies for prostate cancer (PCa) target the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR), although the N-terminal domain (NTD) is the main regulator of AR activity. Targeting the AR NTD directly is a challenge because of its intrinsic disordered nature and the lack of secondary structure and clefts for drugs to bind. Here, we make use of the cochaperone BAG1L that functions through the NTD to develop alternative AR inhibitors. We show that BAG1L binds to a short alpha-helical region of the AR NTD and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by a small molecule 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17) downregulates AR target gene expression and blocks proliferation of AR-positive PCa cells. Targeting a cochaperone as a surrogate to the AR NTD is therefore key to developing novel AR antagonists.

2021-07-01 | GSE159606 | GEO

ANDROGEN RECEPTOR WITH SHORT POLYGLUTAMINE TRACT PREFERABLY ENHANCES WNT/BETA-CATENIN MEDIATED PROSTATE TUMORIGENESIS

Project description:Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we investigated aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of b-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized b-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/b-catenin in combination with short polyQ AR expression in prostate tumorigenesis and provide mechanistic insight into aggressive prostatic tumor development that is frequently observed in African American patients.

2020-03-31 | GSE140963 | GEO

Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

Project description:Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance occurs when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or when constitutively active splice variants lacking the androgen binding domain entirely (e.g. ARV7) is expressed. In this study, we are reporting the discovery of novel AR-NTD covalent inhibitor 1‐chloro‐3‐[(5‐([(2S)‐3‐chloro‐2‐hydroxypropyl]amino)naphthalen‐1‐yl)amino]propan‐2‐ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and its known coactivators and interactors, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule AR-NTD inhibitor for the treatment of CRPC.

2021-07-28 | GSE173331 | GEO

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

Functional mapping of androgen receptor enhancer activity [II]

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 | GSE154632 | GEO

Coactivator condensation at super-enhancers links phase separation and gene control

Project description:Coactivator condensation at super-enhancers links phase separation and gene control

| PRJNA449064 | ENA

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.

2014-12-12 | E-GEOD-52201 | biostudies-arrayexpress

Phase Separation of Ligand-Activated Enhancers Licenses Cooperative Chromosomal Enhancer Assembly

Project description:Phase Separation of Ligand-Activated Enhancers Licenses Cooperative Chromosomal Enhancer Assembly

| PRJNA388759 | ENA