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A Transcriptomic Snapshot of Labor Timing and Development in Human Decidua

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140602 | GEO | 2023/05/01

REPOSITORIES: GEO

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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.

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

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A Transcriptomic Snapshot of Labor Timing and Development in Human Decidua

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