An epigenetic timer of gestation length in mice [CUT&RUN]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242988 | GEO | 2025/01/06
REPOSITORIES: GEO
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Project description:Timing mechanisms in biology remain poorly understood. As one prime example, little is known about the mechanisms that specify how long the gestating uterus will remain quiescent before entering labor1. Our lack of insight into this fundamental question, which applies to all mammalian species, also limits investigation into potential causes of preterm labor, a major human pregnancy complication. Here, we provide evidence that gestation length in mice is determined by an epigenetic timer that runs autonomously within the fibroblasts of the pregnant uterus. The timer is set during the peri-implantation period when select genomic loci establish appropriate levels of the repressive histone mark H3K27me3. These loci then progressively lose H3K27me3, thereby scheduling the uterine cell state transitions and associated gene expression changes of late gestation that are the proximal mediators of labor onset. Overwinding of the timer’s peri-implantation setpoint via genetic ablation of the histone demethylase KDM6B delays these transitions and extends gestation length. These results provide insight into how complex tissues employ epigenetic pathways to specify the timing of discrete biological events. We also anticipate that further dissection of the ways such uterine programming controls gestation length may suggest novel approaches for improving human pregnancy outcomes.
2024-12-20 | GSE242864 | 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: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:Background: Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition. Methods: Gestational d18.0 uteri (n=4) were collected from pregnant wild-type and cyclooxygenase-1 knockout mice. Part of the uterus was used for frozen sections and RNA was isolated from the remainder. Microarray analysis was performed at the Indiana University School of Medicine Genomic Core and analyzed using the Microarray Data Portal. Northern analysis was performed to confirm microarray data and the genes localized in the gravid uterus by in situ hybridization. Results: We identified 277 genes that are abnormally expressed in the gravid d18.0 cyclooxygenase-1 knockout mouse. Nine of these genes are also regulated in the normal murine uterus during the last half of gestation. Many of these genes are involved in the immune response, consistent with an important role of the immune system in parturition. Expression of 4 of these genes; arginase I, IgJ, Tnfrsf9 and troponin; was confirmed by Northern analysis to be mis-regulated during pregnancy in the knockout mouse. In situ hybridization of these genes demonstrated a similar location in the gravid wild-type and Cox-1 knockout mouse uteri. Conclusions: To our knowledge, this is the first work to demonstrate the uterine location of these 4 genes in the mouse during late pregnancy. There are several putative transcription factor binding sites that are shared by many of the 9 genes identified here including; estrogen and progesterone response elements and Ets binding sites. In summary, this work identifies 9 uterine murine genes that may play a role in parturition. The function of these genes is consistent with an important role of the immune system in parturition. Keywords: Comparative genomic hybridization of gravid wild-type and Cox-1 KO mouse uterus
2007-07-24 | GSE8269 | GEO
Project description:Background: Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition. Methods: Gestational d18.0 uteri (n=4) were collected from pregnant wild-type and cyclooxygenase-1 knockout mice. Part of the uterus was used for frozen sections and RNA was isolated from the remainder. Microarray analysis was performed at the Indiana University School of Medicine Genomic Core and analyzed using the Microarray Data Portal. Northern analysis was performed to confirm microarray data and the genes localized in the gravid uterus by in situ hybridization. Results: We identified 277 genes that are abnormally expressed in the gravid d18.0 cyclooxygenase-1 knockout mouse. Nine of these genes are also regulated in the normal murine uterus during the last half of gestation. Many of these genes are involved in the immune response, consistent with an important role of the immune system in parturition. Expression of 4 of these genes; arginase I, IgJ, Tnfrsf9 and troponin; was confirmed by Northern analysis to be mis-regulated during pregnancy in the knockout mouse. In situ hybridization of these genes demonstrated a similar location in the gravid wild-type and Cox-1 knockout mouse uteri. Conclusions: To our knowledge, this is the first work to demonstrate the uterine location of these 4 genes in the mouse during late pregnancy. There are several putative transcription factor binding sites that are shared by many of the 9 genes identified here including; estrogen and progesterone response elements and Ets binding sites. In summary, this work identifies 9 uterine murine genes that may play a role in parturition. The function of these genes is consistent with an important role of the immune system in parturition. Experiment Overall Design: Gestational d18.0 uteri (n=4) were collected from pregnant wild-type and cyclooxygenase-1 knockout mice. Part of the uterus was used for frozen sections and RNA was isolated from the remainder. Microarray analysis (affymetrix 430 2.0) was performed at the Indiana University School of Medicine Genomic Core and analyzed using the Microarray Data Portal. In order to reduce the number of candidate parturition-related genes identified we compared the genes identified as abnormally expressed in the Cox-1 KO uterus to the genes that we had previously identified as changing from gestational d13.5 to d19.0 in the wild-type mouse uterus. Northern analysis was performed to confirm microarray data and the genes localized in the gravid uterus by in situ hybridization.
2008-06-16 | E-GEOD-8269 | biostudies-arrayexpress
Project description:Introduction: Disruption in the synergistic machinery of human parturition can cascade into an ill-timed onset of labor, jeopardizing pregnancy outcomes and contributing to perinatal morbidity and mortality. Parturition is invoked by a phenotypic shift towards a pro-inflammatory predominant state; however, the mechanistic underpinnings as well as tissue-specific role and pathophysiological implications remain elusive. Predicting labor trajectory is further hindered due to confounding by concurrent processes either unrelated or exclusive to advancing gestation. It is thus critical to employ a strategic plan when probing the genetic and environmental tug-of-war that underlies parturition. Methods: We collected human deciduas to explore the genetic control of inflammation within the immunologically-distinct part of the placenta. We performed a genome-wide profiling of the trascriptome to incorporate environmental and fetal stimuli effects on phenotypic divergence. Samples were segregated into term labor (n=16), premature labor (n=16), and nonlaboring C-section (n=18) to distinguish between factors governing gestation duration and those involved in the final pathway of labor. Leveraging the high resolution of next-generation sequencing, we analyzed gene-, isoform-, and network scale-level variability across labor states and then interrogated clinical traits to extract key players in labor timing and development. Results: All samples exhibited a global upregulated expression of adhesion, vascular, humoral, and endocrine genes enriched in the placenta and critical to pregnancy sustenance. Nonlaboring deciduas revealed the most divergent transcriptional landscape, with significant enrichment for dysregulated vacular extracellular matrix remodeling and muscle contractility. Premature deciduas showed a more prominent immune-mediated fetal rejection, infection response, and lipid metabolism signature. Conclusion: Our study provides a comprehensive steady-state snapshot of co-/post-transcriptional changes across various modes of parturition. Using multilayered analytics, it suggests the withdrawal of immune suppression at the maternal-fetal interface during labor development, a process that is further enhanced with pre-existing intrauterine infection and systemic stress to potentially modulate labor timing.
2023-05-01 | GSE140602 | 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:To define the vast landscape of mice pregnancy and labor/parturition associated gene expression transitions, wild type FVB mice uterine tissues from the non-pregnant state (NP) and at E6.5, E8.5, E10.5, E15.5 and E17.5 were analysed using gene expression microarray
2018-11-07 | GSE85934 | GEO
Project description:Timely control of parturition is crucial for maternal and fetal health. Failures on this biological process often result in pregnancy complications including preterm birth, labor dystocia, and health disorders on newborn babies. The myometrium is the muscular structure of the uterus maintaining uterine structural integrity and providing contractile force for parturition. The myometrial structure changes in adaptation to the pregnancy via stage-specific transcriptomic profiles. Data from the mouse model indicate that changes of myometrial epigenomic landscape precedes the adoption of stage-specific gene expression pattern at term. The present study documents the chromatin interaction profiles in the term pregnant not in labor human myometrial tissues at a genome-wide scale.
2024-10-10 | GSE244731 | GEO
Project description:Timely control of parturition is crucial for maternal and fetal health. Failures on this biological process often result in pregnancy complications including preterm birth, labor dystocia, and health disorders on newborn babies. The myometrium is the muscular structure of the uterus maintaining uterine structural integrity and providing contractile force for parturition. The myometrial structure changes in adaptation to the pregnancy via stage-specific transcriptomic profiles. Progesterone signaling plays a crucial role in myometrial remodeling. The present study profiles the transcriptome of human myometrial specimens that are expected to manifest a wide spectrum of progesterone signaling via the RNAseq assay.
2024-10-10 | GSE244728 | GEO