The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression.

The mechanisms whereby progesterone (P), acting via the progesterone receptor (PR), inhibits proinflammatory/contractile gene expression during pregnancy are incompletely defined. Using immortalized human myometrial (hTERT-HM) cells stably expressing wild-type PR-A or PR-B (PR), we found that P significantly inhibited IL-1β induction of the NF-κB target genes, and P-PR transrepression occurred at the level of transcription initiation and was mediated by decreased recruitment of NF-κB p65 and RNA polymerase II to and promoters. However, in cells stably expressing a PR-A or PR-B DNA-binding domain mutant (PR), P-mediated transrepression was significantly reduced, suggesting a critical role of the PR DBD. ChIP analysis of hTERT-HM cells stably expressing PR or PR revealed that P treatment caused equivalent recruitment of PR and PR to and promoters, suggesting that PR inhibitory effects were not mediated by its direct DNA binding. Using immunoprecipitation, followed by MS, we identified a transcriptional repressor, GATA zinc finger domain-containing 2B (GATAD2B), that interacted strongly with PR but poorly with PR P treatment of PR hTERT-HM cells caused enhanced recruitment of endogenous GATAD2B to and promoters. Further, siRNA knockdown of endogenous GATAD2B significantly reduced P-PR transrepression of and Notably, GATAD2B expression was significantly decreased in pregnant mouse and human myometrium during labor. Our findings suggest that GATAD2B serves as an important mediator of P-PR suppression of proinflammatory and contractile genes during pregnancy. Decreased GATAD2B expression near term may contribute to the decline in PR function, leading to labor.