Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec, Canada H4A 3J1.
McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada H3A 0G1.
Dis Model Mech. 2019 Jul 25;12(7):dmm039297. doi: 10.1242/dmm.039297.
Prostate development is controlled by androgens, the eandrogen receptor (AR) and mesenchymal-epithelial signalling. We used chromatin immunoprecipitation sequencing (ChIP-seq) to define AR genomic binding in the male and female mesenchyme. Tissue- and single-cell-based transcriptional profiling was used to define mesenchymal AR target genes. We observed significant AR genomic binding in females and a strong enrichment at proximal promoters in both sexes. In males, there was greater AR binding to introns and intergenic regions as well as to classical AR binding motifs. In females, there was increased proximal promoter binding and involvement of cofactors. Comparison of AR-bound genes with transcriptomic data enabled the identification of novel sexually dimorphic AR target genes. We validated the dimorphic expression of AR target genes using published datasets and confirmed regulation by androgens using organ cultures. AR targets showed variable expression in patients with androgen insensitivity syndrome. We examined AR function at single-cell resolution using single-cell RNA sequencing (scRNA-seq) in male and female mesenchyme. Surprisingly, both AR and target genes were distributed throughout cell subsets, with few positive cells within each subset. AR binding was weakly correlated with target gene expression.
前列腺的发育受雄激素、雄激素受体（AR）和间质-上皮信号的控制。我们使用染色质免疫沉淀测序（ChIP-seq）来确定雄性和雌性间质中 AR 的基因组结合。我们使用基于组织和单细胞的转录谱分析来确定间质 AR 的靶基因。我们观察到女性的 AR 基因组结合存在显著差异，并且在两性中近端启动子都有很强的富集。在男性中，AR 与内含子和基因间区域以及经典的 AR 结合基序的结合更多。在女性中，近端启动子的结合增加了，并且涉及辅助因子。将 AR 结合基因与转录组数据进行比较，使我们能够鉴定出新型的性别二态性 AR 靶基因。我们使用已发表的数据集验证了 AR 靶基因的二态性表达，并使用器官培养证实了它们受雄激素的调节。AR 靶标在雄激素不敏感综合征患者中的表达存在差异。我们使用雄性和雌性间质的单细胞 RNA 测序（scRNA-seq）在单细胞分辨率下检查了 AR 的功能。令人惊讶的是，AR 和靶基因都分布在细胞亚群中，每个亚群中只有少数阳性细胞。AR 结合与靶基因表达的相关性较弱。
