Epigenetic regulation of progesterone receptor isoforms in human parturition

Premature delivery of babies is a major public health concern worldwide due to the associated high mortality and morbidity rates. Of the many agents used and studied for the prevention of preterm birth, progesterone appears to be the most promising agent. Depending on the receptor isoform progesterone binds to, it can either maintain pregnancy by inhibiting myometrial contractions, or initiate parturition by promoting the expression of pro-labour genes. Given the distinct functions of the progesterone receptor isoforms (PR-A and PR-B), and the differential expression of PR isoforms during pregnancy and at labour, the purpose of this project was to investigate potential epigenetic mechanisms that may be responsible for the differential expression of PR isoforms. Findings from this project supported previous reports that PR-A expression is selectively increased in human myometrium at term labour. In correlation, higher levels of activating histone modifications were detected at the promoter region of PR-A at term labour. Specifically, this project showed that labour is associated with an increase in the activating modification, H3K4me3, on the PR-A promoter. Further investigation on histone-modifying enzymes revealed that occupancy of the H3K4me3-selective demethylase, JARID1A, at the PR-A promoter during labour was significantly diminished. Together, this study uncovered an epigenetic mechanism responsible for the differential expression of PR isoforms. Furthermore, preliminary evidence is presented demonstrating that these epigenetic changes may be driven by pro-contractile prostaglandins. Further investigations looking into reversing the effects of histone-modifying enzymes on the PR promoters may prove useful in the development of progesterone-based interventions in preterm births.