Decreased DNA Methylations at the Progesterone Receptor Promoter A Induce Functional Progesterone Withdrawal in Human Parturition

Abstract

The functional interaction of progesterone receptor (PR) isoforms PRA and PRB regulates myometrial transition from the resting state to excitation-contraction to initiate parturition. However, the regulatory mechanisms responsible for maintenance and functional alteration of the PRA and PRB expression levels during human pregnancy and term labor, respectively, remain unknown. Therefore, this study was designed to investigate whether and how epigenetic DNA modifications, specifically methylations, at the PRs' promoter regions contribute to the differential expression of PRA and PRB in laboring term myometrium of humans. Comparative analysis of PRA and PRB messenger RNA (mRNA) expression levels and accompanying changes in their promoters' methylation status was carried out using human myometrial samples from women undergoing singleton, term deliveries by cesarean section, either in the absence of labor (designated as NIL for not-in-labor) or in active labor (designated as IL for in labor). The PRA gene expression was shown to be elevated significantly during labor, while PRB gene expression was unaltered, and this differential expression was accompanied by decreased DNA methylation at the PRA promoter and not at the PRB promoter. In addition, labor-related decreased mRNA expression of the DNA methyltransferase (DNMT) family members DNMT1 and DNMT3a was found, however whether the increased expression of DNMTs directly supports the functional withdrawal of progesterone needs further investigation. Collectively, these data indicate that DNA methylation might represent an important epigenetic mechanism of labor-related differential expression of PRs, thereby mediating the biological process of functional PR withdrawal at term for parturition.

Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

“…All procedures were performed according to the manufacturer’s instructions. The bisulfite converted genomic DNA were subjected to the PCR; 98 °C for 5 min followed by 50 cycles of 98 °C for 10 s, 60 °C for 10 s, and 72 for 30 s. The primer sequences used for PCR were as follows 6,37 .…”

The idiopathic preterm delivery methylation profile in umbilical cord blood DNA

“…It has been suggested that epigenetics is involved in idiopathic preterm delivery in humans [ 10 ]. DNA methylation in myometrium is known to contribute to the functional progesterone withdrawal associated with labor [ 11 , 12 ]. The amnion shows significant methylation changes in the promoter region of the oxytocin receptor gene between preterm and term labor [ 13 ].…”

Progesterone Receptor B Promoter Hypermethylation in Human Placenta After Labor Onset

“…Similar to our results, Mitchell et al 21 found that the PR gene CpG methylation levels in the women who underwent vaginal delivery (IL) were higher than the cesarean delivery group (NIL) in human amnion and decidua. However, Li et al 27 showed there were unaltered at the PRB promoter DNA methylation level, whereas decreased DNA methylation at the PRA promoter in myometrium. At the same time, our results found that 4 samples in the NIL group had a methylated band.…”