Genome-wide analysis of androgen receptor binding and transcriptomic analysis in mesenchymal subsets during prostate...

Area of Science:

• Reproductive Biology
• Endocrinology
• Genomics

Background:

• Prostate development is regulated by androgens, the androgen receptor (AR), and mesenchymal-epithelial signaling.
• Understanding AR's genomic binding and target genes is crucial for elucidating prostate development and disease.

Purpose of the Study:

• To define AR genomic binding sites in male and female prostate mesenchyme.
• To identify mesenchymal AR target genes and characterize their sexually dimorphic expression.
• To investigate AR function at a single-cell resolution.

Main Methods:

• Chromatin immunoprecipitation sequencing (ChIP-seq) to map AR binding.
• Tissue- and single-cell-based transcriptional profiling (scRNA-seq) to identify target genes.
• Ex vivo organ cultures to validate androgen regulation.

Main Results:

• Significant AR genomic binding observed in both sexes, with distinct patterns: females showed enrichment at proximal promoters, while males had greater binding in introns/intergenic regions.
• Identification of novel sexually dimorphic AR target genes, validated through published datasets and ex vivo cultures.
• Single-cell analysis revealed AR and target gene distribution across cell subsets, with weak correlation between AR binding and target gene expression.

Conclusions:

• AR genomic binding and target gene regulation exhibit significant sexual dimorphism in the prostate mesenchyme.
• AR function is complex, with widespread but sparse distribution at the single-cell level.
• Findings offer new perspectives on AR-mediated prostate development and potential implications for androgen insensitivity syndrome.