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Updated: Sep 28, 2025
Chromatin Immunoprecipitation Assay Using Micrococcal Nucleases in Mammalian Cells
Published on: May 10, 2019
Cistrome and transcriptome analysis identifies unique androgen receptor (AR) and AR-V7 splice variant chromatin
Paul Basil1,2, Matthew J Robertson3, William E Bingman3
1Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. basil@connect.hku.hk.
Abstract:
The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and AR-V7. The two AR isoforms shared many targets, but overall had distinct transcriptomes. Optimal induction of novel targets sometimes required more receptor isoform than classical targets such as PSA. The isoforms displayed remarkably different cistromes with numerous differential binding sites. Some of the unique AR-V7 sites were located proximal to the transcription start sites (TSS). A de novo binding motif similar to a half ARE was identified in many AR-V7 preferential sites and, in contrast to conventional half ARE sites that bind AR-V7, FOXA1 was not enriched at these sites. This supports the concept that the AR isoforms have unique actions with the potential to serve as biomarkers or novel therapeutic targets.
Insights
Androgen receptor variant 7 (AR-V7) exhibits unique activities distinct from the full-length androgen receptor (AR) in prostate cancer. These distinct actions suggest AR-V7 could be a potential biomarker or therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Androgen receptor variant 7 (AR-V7) is implicated in castration-resistant prostate cancer (CRPC) and resistance to androgen deprivation therapy.
- Conflicting data exist regarding whether AR-V7 mimics the full-length androgen receptor (AR) or possesses unique functions.
- Previous studies were limited by low AR-V7 levels relative to AR.
Purpose of the Study:
- To directly compare the distinct activities and binding profiles of AR-V7 and AR.
- To investigate the unique transcriptional targets and cistromes of AR and AR-V7.
- To identify novel binding motifs and regulatory elements associated with AR-V7.
Main Methods:
- Utilized LNCaP and VCaP cell lines with inducible AR-V7 expression to match AR levels.
- Compared transcriptomes and cistromes of AR and AR-V7 under controlled expression conditions.
- Performed de novo motif discovery analysis on differential binding sites.
Main Results:
- AR and AR-V7 share some targets but exhibit distinct transcriptomes.
- Optimal induction of novel targets sometimes required higher levels of receptor isoforms.
- AR and AR-V7 displayed significantly different cistromes with numerous differential binding sites.
- A novel binding motif, similar to a half androgen response element (ARE), was identified at unique AR-V7 sites, notably lacking FOXA1 enrichment.
Conclusions:
- AR and AR-V7 possess unique transcriptional activities and distinct cistromes.
- The identified unique AR-V7 binding sites and motifs suggest novel regulatory mechanisms.
- These findings support the potential of AR isoforms as biomarkers and therapeutic targets in prostate cancer.
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