title: miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor.
abstract: Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately down-regulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P(4))/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction-associated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P(4)/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.
authors.affiliation: Department of Biochemistry, North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Renthal
authors.forename: Chien-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Koriand'r C
authors.initials: KC
authors.lastname: Williams
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Janine
authors.initials: J
authors.lastname: Prange-Kiel
authors.forename: Carole R
authors.initials: CR
authors.lastname: Mendelson
mesh_terms: D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007743:Labor, Obstetric / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014590:Uterine Contraction / Q000187:drug effects / Q000235:genetics*; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C533896:MIRN200 microRNA, human; C546363:MIRN429 microRNA, human; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D011374:Progesterone