Bromodomain-containing protein 4 activates androgen receptor transcription and promotes ovarian fibrosis in PCOS

Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcrip-tion is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone-and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation readerBRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1a. BRD4 and HIF-1a inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhib-itor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.

Automated summary

This study found that the upregulation of BRD4 and the resulting AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.