Mus musculus
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ABSTRACT:
PROVIDER: PRJNA134385 | ENA |
REPOSITORIES: ENA
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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
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.
2010-10-30 | GSE25017 | GEO
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
Project description:Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a non-contractile state until term and then surmounts this state to enter labor. Here, we show in mice that dynamic deposition and removal of repressive H3K27me3 chromatin marks in decidual stromal cells dictate both elements of pregnancy success. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets insures uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and, most unexpectedly, generating myofibroblasts and associated wound healing responses. In late gestation, genome-wide H3K27 demethylation allows for target gene upregulation, decidual activation, and labor entry. Strikingly, pharmacological inhibition of this latter process not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a non-inflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders.
2017-10-23 | GSE105444 | GEO
Project description:Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a non-contractile state until term and then surmounts this state to enter labor. Here, we show in mice that dynamic deposition and removal of repressive H3K27me3 chromatin marks in decidual stromal cells dictate both elements of pregnancy success. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets insures uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and, most unexpectedly, generating myofibroblasts and associated wound healing responses. In late gestation, genome-wide H3K27 demethylation allows for target gene upregulation, decidual activation, and labor entry. Strikingly, pharmacological inhibition of this latter process not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a non-inflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders.
2017-10-23 | GSE105455 | GEO
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
Project description:Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. An unbiased transcriptomic analysis of healthy mouse placenta revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysfunction and cellular senescence. We validated these gestational age-associated changes through similar findings in human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma JAR cells, we modeled HIF-1 induction using prolyl hydroxylase inhibitors cobalt chloride (CoCl2) and dimethyloxalylglycine (DMOG), and demonstrated that mitochondrial dysfunction and cellular senescence occur secondary to HIF-1 stabilization. Whole transcriptome analysis revealed that HIF-1 stabilization in JAR cells recapitulated the dysregulation of several pathways observed in aged placenta. Further, conditioned media from cultured trophoblasts following HIF-1 induction is sufficient to induce a contractile phenotype in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may help drive the transition from uterine quiescence to contractility at the onset of labor.
2022-03-29 | GSE199278 | GEO
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF Analysis of 7 overexpression MDCK cells each of them using biological rpelicates (MDCK-E47, Snail2, Snail1, Twist1, Tiwst2, Zeb1, Zeb2)
2014-09-09 | E-GEOD-61217 | biostudies-arrayexpress
Project description:Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. Insufficient interleukin-2 (IL-2) production causes decreased regulatory T cells and permits expansion of autoreactive T cells in the development of SLE. We here show that decreased miR-200a-3p causes IL-2 hypoproduction through directly recruiting ZEB1 or ZEB2 and CtBP2 (ZEB1/ZEB2-CtBP2) complex in SLE T cells. First, we performed RNA sequencing with Illumina Hiseq to obtain the candidate miRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, while its putative targets, ZEB2 and CtBP2 were upregulated in CD4+ T cells in MRL/lpr lupus model mice compared with those of C57BL/6J control mice. ZEB1 and ZEB2 compose ZEB family and suppress various genes including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance and IL-2 defect has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p cause IL-2 defect through ZEB1/ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production though downregulating ZEB1, ZEB2 and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promote IL-2 expression by reducing the bindings of suppressive ZEB1/ZEB2-CtBP2 complex on NRE-A of IL-2 promoter in SLE murine T cells. Interestingly, ZEB1/ZEB2-CtBP2 complex on NRE-A (a negative regulatory element) were significantly upregulated after phorbol-12-myristate-13-acetate and ionomycin (PMA/Iono) stimulation in lupus T cells. Our findings provide a new insight for the epigenetic regulation of IL-2 defect in SLE.
2016-09-23 | GSE87219 | GEO
Project description:Purpose: Characterize the gene expression profile of gastrocnemius muscle in wild type, ZEB1 and ZEB2 knock out mice subjected to 36 hours of fasting Methods: RNA sequencing of RNA from total gastrocnemius muscle after 36h of fasting from the three genotypes used in this study: ZEB1-control, ZEB1-KO, ZEB2-control, ZEB2-KO. Males and females were used from the four genotype (ZEB1flx/flx, ZEB1flx/flx;HSACre, ZEB2flx/flx, ZEB2flx/flx;HSACre). Results: Knockout of ZEB1 or ZEB2 results in differential gene expression in atrophic gastrocnemius muscle Conclusions: Comparison of wild type, ZEB1 and ZEB2 KO muscles displayed differential gene expression profiles after fasting
2023-09-28 | GSE179619 | GEO