title: Exogenous oxytocin modulates human myometrial microRNAs.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: MacIntyre
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Samara
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK.
authors.forename: Sung Hye
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, England, UK.
authors.forename: Natasha
authors.initials: N
authors.lastname: Singh
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, England, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Johnson
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, England, UK. Electronic address: v.terzidou@imperial.ac.uk.
authors.forename: Vasso
authors.initials: V
authors.lastname: Terzidou
mesh_terms: D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007743:Labor, Obstetric / Q000187:drug effects / Q000502:physiology; D035683:MicroRNAs / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D032342:Muscle Cells / Q000378:metabolism; D009215:Myometrium / Q000502:physiology*; D010120:Oxytocics / Q000494:pharmacology*; D010121:Oxytocin / Q000494:pharmacology* / Q000502:physiology; D036801:Parturition / Q000187:drug effects* / Q000502:physiology*; D011247:Pregnancy; D046888:Tissue Array Analysis
chemical_list: D035683:MicroRNAs; D010120:Oxytocics; D010121:Oxytocin
keywords: induction; labor; microRNA; myometrium; oxytocin