The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes

Makieva, Sofia; Dubicke, Aurelija; Rinaldi, Sara F.; Fransson, Emma; Ekman-Ordeberg, Gunvor; Norman, Jane E.

doi:10.1016/j.ajog.2017.02.009

Cited by 19 publications

(19 citation statements)

References 61 publications

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“…The second group consists of transcriptomic studies evaluating differential gene expression during different stages of gestation/parturition in eventless gestations [34][35][36] and ones of particular phenotypes, e.g. cases of PTB (HP:0001622) or PPROM (HP:0001788; OMIM:610504) [37,38]. For a comprehensive evaluation, please refer to the excellent systematic review and meta-analysis of [39].…”

Section: Current Understanding Of Genetics Of Cervical Remodeling Durmentioning

confidence: 99%

“…Considering the known heterogeneity of certain tissues, even the biopsy site may have an impact on the results. For example, a recent study has highlighted that it remains to be resolved whether a PPROM signature can be determined in the cervix as the gene expression patterns in cervical biopsies of PPROM in comparison to preterm labor samples did not share cluster membership, suggesting a distinct genetic signature specific to PPROM pathology [37]. Nonetheless, the authors proposed the notion that the rupture of membranes might be accelerated through PPROM-specific remodeling events within the cervix [37].…”

Section: Current Understanding Of Genetics Of Cervical Remodeling Durmentioning

confidence: 99%

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Genetic landscape of preterm birth due to cervical insufficiency: Comprehensive gene analysis and patient next-generation sequencing data interpretation

et al. 2020

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Preterm delivery is both a traumatizing experience for the patient and a burden on the healthcare system. A condition distinguishable by its phenotype in prematurity is cervical insufficiency, where certain cases exhibit a strong genetic component. Despite genomic advancements, little is known about the genetics of human cervix remodeling during pregnancy. Using selected gene approaches, a few studies have demonstrated an association of common gene variants with cervical insufficiency. However, until now, no study has employed comprehensive methods to investigate this important subject matter. In this study, we asked: i) are there genes reliably linked to cervical insufficiency and, if so, what are their roles? and ii) what is the proportion of cases of non-syndromic cervical insufficiency attributable to these genetic variations? We performed next-generation sequencing on 21 patients with a clinical presentation of cervical insufficiency. To assist the sequencing data interpretation, we retrieved all known genes implicated in cervical functioning through a systematic literature analysis and additional gene searches. These genes were then classified according to their relation to the questions being posed by the study. Patients' sequence variants were filtered for pathogenicity and assigned a likelihood of being contributive to phenotype development. Gene extraction and analysis revealed 12 genes primarily linked to cervical insufficiency, the majority of which are known to cause collagenopathies. Ten patients carried disruptive variants potentially contributive to the development of non-syndromic cervical insufficiency. Pathway enrichment analysis of variant genes from our cohort revealed an increased variation burden in genes playing roles in tissue mechanical and biomechanical properties, i.e. collagen biosynthesis and cell-extracellular matrix communications. Consequently, the proposed idea of cervical insufficiency being a subtle form of collagenopathy, now strengthened by our genetic findings, might open up new opportunities for improved patient evaluation and management.

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Section: Current Understanding Of Genetics Of Cervical Remodeling Durmentioning

confidence: 99%

Section: Current Understanding Of Genetics Of Cervical Remodeling Durmentioning

confidence: 99%

Genetic landscape of preterm birth due to cervical insufficiency: Comprehensive gene analysis and patient next-generation sequencing data interpretation

et al. 2020

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“…We identified 54 studies through the first phase of our literature search, but only 10 data sets that met all inclusion criteria. All excluded studies are listed in Additional File 1 with reasons for exclusion and the 10 data sets used in our pilot analysis are outlined in Table 1 [33][34][35][36][37][38][39][40][41][42][43][44][45][46].…”

Section: Study Identificationmentioning

confidence: 99%

“…SNP-based data containing P-values and effect sizes were mapped to genes with MAGMA, as outlined in the Zhang et al supplementary methods (http://ctg.cncr.nl/software/magma)[35,47,48].Transcriptomics. Gene expression data from microarray experiments were accessed via GEO(https://www.ncbi.nlm.nih.gov/geo/) and re-analyzed using the GEO2R plugin (https://www.ncbi.nlm.nih.gov/geo/info/geo2r.html)[36][37][38][39]. Raw RNA-seq data from Ackerman et al were analyzed in-house with custom scripts[33].Epigenomics.…”

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confidence: 99%

integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth

Eidem

Steenwyk

Wisecaver

et al. 2018

Preprint

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Background:The integration of high-quality, genome-wide analyses offers a robust approach to elucidating genetic factors involved in complex human diseases. Even though several methods exist to integrate heterogeneous omics data, most biologists still manually select candidate genes by examining the intersection of lists of candidates stemming from analyses of different types of omics data that have been generated by imposing hard (strict) thresholds on quantitative variables, such as P-values and fold changes, increasing the chance of missing potentially important candidates. Methods:To better facilitate the unbiased integration of heterogeneous omics data collected from diverse platforms and samples, we propose a desirability function framework for identifying candidate genes with strong evidence across data types as targets for follow-up functional analysis. Our approach is targeted towards disease systems with sparse, heterogeneous omics data, so we tested it on one such pathology: spontaneous preterm birth (sPTB). Results:We developed the software integRATE, which uses desirability functions to rank genes both within and across studies, identifying well-supported candidate genes according to the cumulative weight of biological evidence rather than based on imposition of hard thresholds of key variables. Integrating 10 sPTB omics studies identified both genes in pathways previously suspected to be involved in sPTB as well as novel genes never before linked to this syndrome.integRATE is available as an R package on GitHub (https://github.com/haleyeidem/integRATE).3 Conclusions: Desirability-based data integration is a solution most applicable in biological research areas where omics data is especially heterogeneous and sparse, allowing for the prioritization of candidate genes that can be used to inform more targeted downstream functional analyses.

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“…Prevention of pregnancy complications through enhanced understanding and appropriate intervention is of critical importance to improve both maternal and neonatal outcomes. The causes of PPROM are multifactorial and include: pathologic anatomical remodeling 3, 4 , altered membrane morphology 5–10 , complications from invasive procedures 11 , inflammation 12–14 , and genetic factors 15–17 . Although the mechanisms of PPROM are not well-understood, infection in the fetal membranes has been implicated as an early event in the pathogenesis of PPROM and/or preterm labor 18–25 .…”

Section: Introductionmentioning

confidence: 99%

Infection-induced thrombin production: a potential novel mechanism for preterm premature rupture of membranes (PPROM)

Feng

Allen

Marinello

et al. 2018

American Journal of Obstetrics and Gynecology

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Background Preterm premature rupture of membranes (PPROM) is a leading contributor to maternal and neonatal morbidity and mortality. Epidemiologic and experimental studies have demonstrated that thrombin causes fetal membrane weakening and subsequently PPROM. Although blood is suspected as the likely source of thrombin in fetal membranes and amniotic fluid of patients with PPROM, this has not been proven. Ureaplasma Parvum (U. parvum) is emerging as a pathogen involved in prematurity, including PPROM, but until now, prothrombin production directly induced by bacteria in fetal membranes has not been described. Objectives This study was designed to investigate whether U. parvum exposure can induce prothrombin production in fetal membranes cells. Study Design Primary fetal membrane cells (amnion epithelial, chorion trophoblast, and decidua stromal) or full-thickness fetal membrane tissue explants from elective, term, uncomplicated cesarean deliveries were harvested. Cells or tissue explants were infected with live U. parvum (1 × 105, 1 × 106, or 1 × 107 colony forming units (cfu)/ml) or lipopolysaccharide (Escherichia coli J5, L-5014, Sigma, 100 ng/ml or 1000 ng/ml) for 24 hours. Tissue explants were fixed for immunohistochemistry staining of thrombin/prothrombin. Fetal membrane cells were fixed for confocal immunofluorescent staining of the biomarkers of fetal membrane cell types and thrombin/prothrombin. Protein and mRNA were harvested from the cells and tissue explants for Western blot or qRT-PCR to quantify thrombin/prothrombin protein or mRNA production, respectively. Data are presented as mean values ± standard errors of mean. Data were analyzed using one-way ANOVA with post hoc Dunnett’s test. Results Prothrombin production and localization was confirmed by Western blot and immunostainings in all primary fetal membrane cells and tissue explants. Immunofluorescence observations revealed a perinuclear localization of prothrombin in amnion epithelial cells. Localization of prothrombin in chorion and decidua cells was perinuclear and cytoplasmic. Prothrombin mRNA and protein expression in fetal membranes was significantly increased by U. parvum, but not lipopolysaccharide, treatments in a dose-dependent manner. Specifically, U. parvum at a dose of 1×107 cfu/ml significantly increased both prothrombin mRNA (fold changes in amnion: 4.1±1.9; chorion: 5.7±4.2; decidua: 10.0±5.4; FM: 9.2±3.0) and protein expression (fold changes in amnion: 138.0±44.0; chorion: 139.6±15.1; decidua: 56.9±29.1; fetal membrane: 133.1±40.0) compared to untreated controls. U. parvum at a dose of 1×106 cfu/ml significantly upregulated prothrombin protein expression in chorion cells (fold change: 54.9±5.3) and prothrombin mRNA expression in decidua cells (fold change: 4.4±1.9). Conclusions Our results demonstrate that prothrombin can be directly produced by fetal membrane amnion, chorion, and decidua cells. Further, prothrombin production can be stimulated by U. parvum exposure in fetal membranes. These findings represent a potentia...

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The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes

Cited by 19 publications

References 61 publications

Genetic landscape of preterm birth due to cervical insufficiency: Comprehensive gene analysis and patient next-generation sequencing data interpretation

Genetic landscape of preterm birth due to cervical insufficiency: Comprehensive gene analysis and patient next-generation sequencing data interpretation

integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth

Infection-induced thrombin production: a potential novel mechanism for preterm premature rupture of membranes (PPROM)

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