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The 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, 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 contraction-associated genes 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 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 novel progesterone/PR- mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth.

ORGANISM(S): Mus musculus

PROVIDER: GSE25017 | GEO | 2010/10/30

SECONDARY ACCESSION(S): PRJNA134385

REPOSITORIES: GEO

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The miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

Project description:Throughout 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 contraction-associated genes 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 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 novel progesterone/PR- mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth. RNA was purified from mouse myometrium (miRNeasy kit, Qiagen). miRNA microarray was performed (LC Sciences) on 18 biological replicates of murine myometrium at 15.5 dpc and an equal number of replicates at 18.5 dpc. Gene expression microarray assays were performed (UT Southwestern Medical Center) on the same 36 samples as detailed further in SI Materials and Methods.

2010-10-30 | E-GEOD-25017 | biostudies-arrayexpress

Mus musculus

Project description:The miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor

| PRJNA134385 | ENA

Myometrial Progesterone Receptor Isoform B Regulates the Phospholipase C Pathway and Suppresses Uterine Contractility

Project description:Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. Progesterone is necessary to suppress uterine contractions to prevent premature labor. As humans maintain high levels of progesterone throughout parturition, a functional progesterone withdrawal hypothesis suggests that relative levels of myometrial progesterone receptor isoforms PGR-A and PGR-B switch at parturition, where PGR-B promotes a relaxed state and PGR-A result in increased uterine contractility. Our objective is to determine the effects of altered levels of PGR-B and PGR-A in the mouse myometrium on pregnancy and parturition using transgenic mouse models in which the relative levels of these isoforms are altered specifically in the myometrium. Overexpression of PGR-B is associated with a markedly increased gestational length compared to control mice. In both ex vivo and in vivo experiments, myometrium of PGR-B overexpressing mice have prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, overexpression of PGR-A is associated with an increase in uterine contractility without a change in gestational length. Uterine RNAseq at mid-pregnancy identified isoform-specific downstream targets and genes that were commonly regulated by both PGR isoforms. Gene signature analyses further revealed that PGR-B promotes muscle relaxation and that PGR-A is pro-inflammation. High levels of PGR-B manifest a genetic profile of a blunted phospholipase C pathway that mediates oxytocin and angiotensin II induced muscle contraction. These findings provided in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor.

2021-02-24 | GSE146634 | GEO

Effect of prolonged stretch on transcript profile of human pregnant myometrium

Project description:Context: Increased uterine stretch appears to increase the risk of preterm labour, but the mechanism is unknown. Objectives: To identify a targetable mechanism mediating the effect of stretch on human myometrium. Design: Myometrial explants, prepared from biopsies obtained at elective caesarean delivery, were either studied acutely, or were maintained in prolonged culture (up to 65 h) under tension with either a 0.6 g or 2.4 g mass, and compared using in vitro contractility, whole genome array, and qRT-PCR. Results: Increased stretch for 24 or 65 h increased potassium-induced and oxytocin-induced contractility. Gene array identified 62 differentially expressed transcripts after 65 h exposure to increased stretch. Two probes for gastrin-releasing peptide (GRP), a known stimulatory agonist of smooth muscle, were among the top five up-regulated by stretch (3.4-fold and 2.0-fold). Up-regulation of GRP by stretch was confirmed in a separate series of 10 samples using qRT-PCR (2.8-fold, P = 0.01). GRP stimulated contractions acutely when added to freshly obtained myometrial strips in 3 out of 9 cases, but Western blot demonstrated expression of the GRP receptor in 9 out of 9 cases. Prolonged incubation of stretched explants in the GRP antagonists PD-176252 or RC-3095 (65 and 24 h respectively) significantly reduced potassium chloride and oxytocin-induced contractility. Conclusion: Stretch of human myometrium increases contractility and stimulates the expression of a known smooth muscle stimulatory agonist, GRP. Incubation of myometrium in GRP receptor antagonists ameliorates the effect of stretch. GRP may be a target for novel therapies to reduce the risk of preterm birth in multiple pregnancy. 9 paired samples of human myometrium cultured under low (0.6g) or high (2.4g) tension

2012-06-14 | E-GEOD-31329 | biostudies-arrayexpress

Fetal cortical transcriptomic changes after oxytocin induced aberrant uterine contractility

Project description:We report changes in the fetal brain cortical transcriptome after oxytocin-induced aberrant uterine contractility using unbiased RNA-seq analysis.

2020-03-02 | GSE146155 | GEO

Intra-amniotic Balloon Inflation Induces an Inflammatory “Pulse” and Labor in Nonhuman Primates

Project description:Uterine stretch is thought to induce preterm labor in women with twin and higher order pregnancies, but the pathophysiology remains unclear. We investigated the pathogenesis of stretch-induced preterm birth for the first time in a pregnant nonhuman primate model.

2015-09-11 | GSE63274 | GEO

Effect of prolonged stretch on transcript profile of human pregnant myometrium

2012-06-15 | GSE31329 | GEO

The miR-200 Family and their Targets in Regulation of Type II Cell Differentiation in Human Fetal Lung

Project description:Type II cell differentiation and expression of the major surfactant protein, SP-A, in midgestation human fetal lung (HFL) are markedly induced by cAMP and inhibited by TGF-β. cAMP induction of SP-A promoter activity is mediated by increased phosphorylation and in vivo binding of TTF-1/Nkx2.1, a critical transcription factor in lung development. To further define mechanisms for developmental induction of surfactant synthesis in HFL, herein, we investigated the potential role of microRNAs (miRNAs, miRs). To identify and characterize differentially regulated miRNAs in mid-gestation HFL explants during type II pneumocyte differentiation in culture, we performed miRNA microarray analysis of RNA isolated from epithelial cells from midgestation HFL explants before and after culture ± Bt2cAMP. Interestingly, the miR-200 family was significantly upregulated during type II cell differentiation; miR-200 family induction was inversely correlated with expression of its known targets, transcription factors ZEB1 and ZEB2, and TGF-b2. miR-200 antagonists inhibited TTF-1 and SP-A expression and upregulated TGF-β2 and ZEB1 expression in type II cells. Overexpression of ZEB1 in cultured type II cells decreased DNA binding of endogenous TTF-1, blocked cAMP stimulation of SP-A and inhibited miR-200 expression,whereas, cAMP markedly inhibited ZEB1/2 and TGF-β. Importantly, overexpression of ZEB1 or miR-200 antagonists in HFL type II cells markedly suppressed accumulation of lamellar bodies, organelles that store surfactant. Our findings suggest that the miR-200 family and ZEB1, which exist in a double-negative feedback loop regulated by TGF-β, serve important regulatory roles in the developmental regulation of type II cell differentiation and SP-A expression in HFL.

2015-10-01 | GSE61183 | GEO

Fetal cortical transcriptomic changes after oxytocin induced aberrant uterine contractility

Project description:Fetal cortical transcriptomic changes after oxytocin induced aberrant uterine contractility

| PRJNA609567 | ENA

Transcription profiling of human myometrium from samples obtained at term (n=6) or preterm (n=6) with and without labor

Project description:Distinct processes govern the transition from myometrial quiescence to activation during both term and preterm labor. We sought the specific gene sets responsible for initiating term and preterm labor, along with a core set of effector genes necessary for labor independent of gestational age and the underlying trigger. The Effector Gene Set consisted of 49 genes present in both preterm and term labor but absent from non-labor samples. 122 genes were specific to preterm labor (Preterm Initiator Set) and 229 to term labor (Term Initiator Set). The Term Initiator and the Effector Sets reflected predominantly inflammatory processes. Surprisingly, the Preterm Initiator Gene Set reflected molecular and biological events almost exclusive of inflammation. Preterm and term labor differ dramatically in their unique, initiator gene profiles, suggesting alternative pathways underlie these events. Inflammatory processes are ubiquitous to the Term Initiator and the Effector Gene Sets, supporting the idea term parturition is an inflammatory process. The absence of inflammatory processes in the Preterm Initiator Set suggests inflammation is secondary to processes triggering spontaneous preterm birth, and could explain the lack of therapeutic efficacy associated with anti inflammatory/antibiotic regimens. Experiment Overall Design: Myometrial gene expression was analyzed from samples obtained at term (n=6) or preterm (n=6) with and without labor using cDNA microarrays. Patients in preterm labor all had intra amniotic inflammation. Gene sets were generated using logical operations within a functional mapping tool (MetaCoreâ¢, GeneGo, St. Joseph, MI). Relevant gene sets were validated with quantitative real-time polymerase chain reaction.

2008-10-26 | E-GEOD-9159 | biostudies-arrayexpress

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