title: The microRNA (miR)-199a/214 cluster mediates opposing effects of progesterone and estrogen on uterine contractility during pregnancy and labor.
abstract: Progesterone (P(4)) and estradiol-17β (E(2)) play critical and opposing roles in regulating myometrial quiescence and contractility during pregnancy and labor. Although these contrasting hormonal effects are likely mediated via differential regulation of inflammatory and contractile genes, the underlying mechanisms remain incompletely understood. Recently we discovered that targets of the microRNA (miR)-200 family, transcription factors zinc finger E-box binding homeobox (ZEB)-1 and ZEB2, serve as P(4)/progesterone receptor-mediated regulators of uterine quiescence during pregnancy. In the present study, we found that levels of the clustered miRNAs, miR-199a-3p and miR-214, were significantly decreased in laboring myometrium of pregnant mice and humans and in an inflammatory mouse model of preterm labor, whereas the miR-199a-3p/miR-214 target, cyclooxygenase-2, a critical enzyme in synthesis of proinflammatory prostaglandins, was coordinately increased. Overexpression of miR-199a-3p and miR-214 in cultured human myometrial cells inhibited cyclooxygenase-2 protein and blocked TNF-α-induced myometrial cell contractility, suggesting their physiological relevance. Notably, E(2) treatment of ovariectomized mice suppressed, whereas P(4) enhanced uterine miR-199a-3p/214 expression. Intriguingly, these opposing hormonal effects were mediated by ZEB1, which is induced by P(4), inhibited by E(2) and activates miR199a/214 transcription. Together, these findings identify miR-199a-3p/miR-214 as important regulators of myometrial contractility and provide new insight into strategies to prevent preterm birth.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Koriand'r C
authors.initials: KC
authors.lastname: Williams
authors.forename: Nora E
authors.initials: NE
authors.lastname: Renthal
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Carole R
authors.initials: CR
authors.lastname: Mendelson
mesh_terms: D000818:Animals; D001483:Base Sequence; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007743:Labor, Obstetric / Q000187:drug effects* / Q000235:genetics*; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009215:Myometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects* / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D004967:Estrogens; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; C534781:Mirn214 microRNA, mouse; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C531408:mirn199 microRNA, human; D011374:Progesterone; D051546:Cyclooxygenase 2