Term myometrium is characterized by increased activating epigenetic modifications at the progesterone receptor-A promoter

• Published in: Molecular human reproduction Vol. 18; no. 7-8; pp. 401 - 409
• Main Authors: CHAI, S. Y, SMITH, R, ZAKAR, T, MITCHELL, C, MADSEN, G
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2012
• Subjects: Biological and medical sciences; Embryology: invertebrates and vertebrates. Teratology; Epigenesis, Genetic; Female; Fundamental and applied biological sciences. Psychology; Histones - genetics; Histones - metabolism; Humans; Labor Onset - metabolism; Myometrium - metabolism; Pregnancy; Pregnancy Trimester, Third; Progesterone - metabolism; Promoter Regions, Genetic; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Human; Myometrium; epigenetic; progesterone receptors; histone modifications; Labor; labour; Promoter; Uterus; Female genital system; Epigenetics; Histone; Hormonal receptor
• ISSN: 1360-9947; 1460-2407
• DOI: 10.1093/molehr/gas012

Term human myometrial expression of progesterone receptor (PR)-A is increased relative to PR-B, and as PR-A is a repressor of progesterone action mediated through PR-B, this increase may mediate the withdrawal of progesterone action and precipitate the onset of labour. PR-A and PR-B expression is regulated by two separate promoters of the PR gene. We hypothesized that epigenetic histone modifications at the two promoters contribute to the labour-associated regulation of PR-A and PR-B expression in term myometrium. PR total, PR-B and PR-A mRNA levels were determined using quantitative real-time PCR, and chromatin immunoprecipitation was used to determine the levels of activating and repressive histone modifications at the PR-A and PR-B promoters in human myometrial samples not in labour (n = 4) and in labour (n = 4). Chromatin extracts were immunoprecipitated with antibodies against activating (histone H3 and H4 acetylation and histone H3 lysine 4 trimethylation), and repressive (histone H3 lysine 9 trimethylation, histone H3 lysine 27 trimethylation and asymmetrical histone H3 arginine 2 dimethylation) histone modifications. PR-A mRNA levels increased during labour, while PR-B mRNA levels remained constant resulting in an increase of PR-A/PR-B mRNA ratio, as expected. Regardless of labour status, significantly higher levels of the activating histone modifications were found at the PR-A promoter compared with the PR-B promoter (P <0.001). H3K4me3 increased significantly at both promoters with labour onset (P =0.001). Low levels of the repressive histone modifications were also present at both promoters, with no labour-associated changes observed. Our data indicate that the PR-A promoter is epigenetically marked for activation in term myometrium more extensively than the PR-B promoter, and that labour is associated with an increase in H3K4me3 activating modification, consistent with the previously described increase in PR protein at this time.