Increased progesterone receptor A expression in labouring human myometrium is associated with decreased promoter occupancy by the histone demethylase JARID1A

Abstract

Progesterone regulates female reproductive function predominantly through two nuclear progesterone receptors (PRs), PR-A and PR-B. During human parturition myometrial PR expression is altered to favour PR-A, which activates pro-labour genes. We have previously identified histone H3 lysine 4 trimethylation (H3K4me3) as an activator of myometrial PR-A expression at labour. To further elucidate the mechanisms regulating PR isoform expression in the human uterus at labour, we have (i) determined the methylation profile of the cytosine-guanine dinucleotides (CpG) island in the promoter region of the PR gene and (ii) identified the histone-modifying enzymes that target the H3K4me3 mark at the PR promoters in term and preterm human myometrial tissues obtained before and after labour onset. Bisulphite sequencing showed that despite overall low levels of PR CpG island methylation, there was a significant decrease in methylated CpGs with labour in both preterm (P < 0.05) and term (P < 0.01) groups downstream of the PR-B transcription start site. This methylation change was not associated with altered PR-B expression, but may contribute to the increase in PR-A expression with labour. Chromatin immunoprecipitation revealed that the histone methyltransferase, SET and MYND domain-containing protein 3 (SMYD3), bound to the PR gene at significantly higher levels at the PR-A promoter compared with the PR-B promoter (P < 0.010), with no labour-associated changes observed. The H3K4 demethylase, Jumonji AT-rich interactive domain 1A (JARID1A), also bound to the PR-A, but not to the PR-B promoter prior to term labour, and decreased significantly at the onset of labour (P = 0.014), providing a mechanism for the previously reported increase in H3K4me3 level and PR-A expression with labour. Our studies suggest that epigenetic changes mediated by JARID1A, SMYD3 and DNA methylation may be responsible, at least in part, for the functional progesterone withdrawal that precipitates human labour.

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…JARID1B appears to be a negative regulator of hematopoietic stem cell (HSC) activity and is required for HSC differentiation [112], although its function here remains controversial [113]. Roles for JARID1B have also been described in adult neural stem cell maintenance [114] and angiogenesis [116], and JARID1A participates in suppression of uterine contraction [115]. …”

The impact of progesterone and RU-486 on classic pro-labour proteins & contractility in human myometrial tissues during 24-hour exposure to tension & interleukin-1β

“…Functional P4 withdrawal at parturition is commonly characterised by an increase in PR-A:PR-B expression ratio (Mesiano et al , 2002, Rezapour et al , 1997, Tan et al, 2012. PR function is also affected by differential histone modification of PR gene promoters (Chai et al , 2014, Chai et al , 2012 and the phosphorylation status of PR-A protein at its Ser345 residue (Amini et al , 2016); both have been examined for their roles in the switch from pro-pregnancy to pro-labour state within myometrial cells in relation to inflammation.…”

Progesterone Receptor Signaling in Uterine Myometrial Physiology and Preterm Birth

“…This is also in line with the observation that PGR-A mRNA levels increase over the course of pregnancy while the PGR-B mRNA abundance has minimal change (Chai et al, 2012). On the PGR-A promoter, laboring human myometrium exhibits higher H3K4me3 levels and reduced occupancy of the H3K4 demethylase, Jumonji AT-rich interactive domain 1A (JARID1A, also known as KDM5A), compared with quiescent myometrium (Chai et al, 2014). Because JARID1A can repress PGR expression in MCF-7 cells (Stratmann and Haendler, 2011), it is proposed that the reduced JARID1A occupancy may result in higher levels of H3K4me3, increased enhancer activities and subsequent further induction of PGR-A transcription in laboring myometrium.…”