Exogenous oxytocin modulates human myometrial microRNAs - 24/04/15

Doi : 10.1016/j.ajog.2015.03.015

Joanna R. Cook, MRCOG ^a, David A. MacIntyre, PhD ^a, Eleni Samara, MSc ^a, Sung Hye Kim, PhD ^a, Natasha Singh, MRCOG ^a,^b, Mark R. Johnson, MRCOG, PhD ^a,^b, Phillip R. Bennett, FRCOG, PhD ^a, Vasso Terzidou, MRCOG, PhD ^a,^b,^⁎
^a Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK
^b Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, England, UK

^∗Corresponding author: Vasso Terzidou, MRCOG, PhD.

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Abstract

Objective

MicroRNAs (miRNAs) play a modulatory role in pathways that lead to labor onset, although oxytocin is known to modulate gene expression within the myometrium. We aimed to identify miRNAs whose expression is regulated by oxytocin in pregnant human myometrium.

Study Design

Myometrial miRNA expression profiles were compared between samples collected from women at term before the onset of labor (no labor; n = 8) and after labor onset after early exogenous oxytocin treatment (n = 8). Multivariate modelling was used to assess differences in miRNA profiles. Biologic validation was undertaken on 3 independent patient cohorts (no labor, n = 10; labor induced with oxytocin, n = 8; and spontaneous labor with no oxytocin treatment, n = 10). In vitro studies that used primary myocytes were undertaken to assess target miRNA expression after oxytocin treatment. Target genes of candidate miRNAs were identified in silico and cross-referenced with genes that are known to be associated with labor or expressed in myometrium.

Results

In total, 1309 miRNAs were analyzed by microarray, of which 494 were detected in human myometrium. Multivariate modeling identified 12 target miRNAs the differential expression of which was most responsible for the observed separation of the 2 patient populations in the primary discovery cohorts. Biologic validation in the independent secondary sample cohorts showed that oxytocin independently regulated 5 miRNAs (hsa-miR-146b-3p, hsa-miR-196b-3p, hsa-miR-223-3p, hsa-miR-873-5p, and hsa-miR-876-5p). Additionally, hsa-miR-146b-3p was increased both in labor that was induced with oxytocin and in myometrium from spontaneous labor with no oxytocin treatment compared with no labor samples. Four of the validated miRNAs (hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR-196b-3p, and hsa-miR-876-5p) were expressed in primary human myocytes; oxytocin treatment of these cells replicated the directional changes that were observed in vivo.

Conclusion

Oxytocin alters the expression of a unique set of myometrial miRNAs. These results suggest a further role for oxytocin as a signaling molecule that is involved in the regulation of gene expression during parturition.

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Key words : induction, labor, microRNA, myometrium, oxytocin

Plan

Materials and Methods

Study design

RNA isolation

In vitro modeling: cell culture and cell treatments

Microarray

Real-time qRT-PCR for miRNA

Statistical analysis

Identification of potential target genes

Results

Exogenous oxytocin modulates the expression of a subset of miRNAs in human myometrium

The laboring myometrial miRNA profile of women who were treated with oxytocin differs from those in spontaneous labor

Oxytocin treatment regulates miRNA expression in human myocytes

Potential targets of oxytocin-regulated miRNAs

Comment

	Supported by a research training fellowship from Action Medical ResearchGN2248 (J.R.C.), by an MRC Career Development AwardMR/L009226/1 (D.A.M.), by the Borne Charity, Chelsea and Westminster Hospital (N.S. and M.R.J.), by the Genesis Research Trust (V.T.), and by the Imperial Healthcare NHS Trust NIHR Biomedical Research Centre (D.A.M.; P.R.B.; V.T.).
	P.R.B. and V.T. work as consultants to GlaxoSmithKline; P.R.B. works as a consultant to ObsEva, pharmaceutical companies with an interest in the pharmacologic effects of oxytocin and oxytocin antagonists. The remaining authors report no conflict of interest.
	Cite this article as: Cook JR, MacIntyre DA, Samara E, et al. Exogenous oxytocin modulates human myometrial microRNAs. Am J Obstet Gynecol 2015;212:••••.