Differential DNA methylation pattern in the A and B promoters of the progesterone receptor is associated with differential mRNA expression in the female rat hypothalamus during proestrus

Abstract

In rodents, the display of reproductive behavior occurs during the proestrus–estrus transition of the estrus cycle. This behavior is regulated by estradiol and progesterone mainly via their intracellular receptors. Two isoforms of the progesterone receptor have been described (A and B), and they have different promoters for their regulation. It has been demonstrated that the mRNA for both isoforms changes during the proestrus–estrus transition. It has been recently established that DNA methylation can be transient and cyclical in gene promoters, however, these changes have only been reported in vitro but not in physiological models. The aim of this study was to analyze the pattern of DNA methylation in the PR (A and B) promoter regions during the proestrus–estrus transition in the rat hypothalamus and its correlation with the regulation of mRNA expression. The results demonstrated a differential mRNA expression of the progesterone receptor (A and B) isoforms. The expression of total PR did not change significantly during the proestrus day, while the expression of isoform B increased significantly at 17:00h, followed by a significant decrease at 21:00h of the proestrus day. Interestingly, we also found that the isoform A promoter was mainly unmethylated at all studied time points. In contrast, the isoform B promoter showed a transient methylation increase during the evening of proestrus. The overall results indicate that there is a switch of progesterone receptor isoforms expression during the evening of proestrus that is related to the differential gene methylation patterns of their promoter regions, mainly for the isoform B promoter.