Androgen stimulation rapidly reorganizes temporal 3D genome and epigenome states to trigger AR-mediated transcription in prostate cancer.

IntroductionAndrogen receptor (AR)-mediated transcription drives prostate cancer progression and remains a key therapeutic target. AR is activated by androgens, translocating to the nucleus to bind DNA regulatory elements (AREs) and initiate transcription. This process involves co-regulatory proteins, pioneer factors like FOXA1, epigenetic modifications, and 3D chromatin interactions. However, the temporal coordination of AR and co-regulatory binding factors, epigenomic modifications, and 3D chromatin dynamics during AR-mediated transcription remains unclear. ResultsUsing a time-course model of androgen stimulation in LNCaP prostate cancer cells, we integrated temporal multi-omics datasets into the MOFA+ framework to investigate AR-mediated transcriptional dynamics. Our analyses uncovered a critical role for rapid AR binding at gene promoters in driving nascent transcription of AR target genes. We demonstrated that AR binding is preceded by nucleosome H3K27 acetylation flanking androgen response elements, which are constitutively marked by FOXA1 binding. Notably, we identified a temporal early switch in nascent transcription post-androgen stimulation, from MYC to AR target genes, likely mediated by transient androgen-induced 3D chromatin interactions. SignificanceThese findings reveal that androgen stimulation rapidly reorganizes 3D chromatin structure and differential MYC and AR transcription factor binding to trigger three distinct patterns of temporal epigenome states associated with the establishment of AR-mediated transcription in prostate cancer. These insights advance understanding of AR regulation in prostate cancer and contribute to a deeper understanding of the temporal relationship between MYC and AR transcriptional regulation in hormone-driven cancers.