Post-Transcriptional Regulation by microRNAS in Pregnancy and Parturition

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dc.contributor.advisorMendelson, Carole R.en
dc.creatorRenthal, Nora Edwardsen
dc.date.accessioned2012-08-15T14:29:13Z
dc.date.available2012-08-15T14:29:13Z
dc.date.issued2012-08-15
dc.description.abstractThroughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, while spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and negatively impact PR function. In this study, we uncovered a new regulatory pathway whereby miRNAs serve as hormonally-modulated and conserved mediators of contractile gene regulation in the pregnant uterus from mouse to 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 downregulated targets, zinc finger E-box binding homeobox proteins, ZEB1 and ZEB2, which act as transcriptional repressors. We also observed upregulation of the miR-200 family and downregulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly upregulated by the action of P4/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibited expression of the contraction-associated genes, oxytocin receptor and connexin-43 and blocked oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets ZEB1 and ZEB2 as novel P4/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth.en
dc.identifier.oclc812607576
dc.identifier.urihttps://hdl.handle.net/2152.5/1113
dc.language.isoenen
dc.subjectLabor, Obstetricen
dc.subjectMicroRNAsen
dc.subjectTranscription Factorsen
dc.titlePost-Transcriptional Regulation by microRNAS in Pregnancy and Parturitionen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2012-07-10
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineGenetics and Developmenten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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