Transcriptomisc Reveals Myometrial Topologically Associated Domains linked to the Onset of Human Term Labor
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PROVIDER: PRJNA775985 | ENA |
REPOSITORIES: ENA
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Project description:Changes in cell phenotype are thought to occur through the expression of groups of co-regulated genes within Topologically Associated Domains (TADs). In this paper we locate genes expressed within the myometrium of the human uterus during the onset of term labor into TADs. Transformation of the myometrial cells of the uterus into a contractile phenotype during term human labor is the result of a complex interaction of different epigenomic and genomic layers. Recent work suggests that the transcription factor RelA lies at the top of this regulatory network. Using deep RNAseq analysis of myometrial samples obtained at term from women undergoing caesarean section prior to or after the onset of labor we have identified evidence for how other gene expression regulatory elements interact with transcription factors in the labor phenotype transition. Gene set enrichment analysis of our RNAseq data identified three modules of enriched genes (M1, M2 and M3) which in gene ontology studies are linked to matrix degradation, smooth muscle and immune gene signatures. These genes were predominantly located within chromosomal TADs suggesting co-regulation of expression. Our transcriptomic analysis also identified significant differences in the expression of long-non-coding RNAs (lncRNA), microRNAs (miRNA) and transcription factors that were predicted to target genes within the TADs. Additionally, network analysis revealed 14 new lncRNA (MCM3AP-AS1, TUG1, MIR29B2CHG, HCG18, LINC00963, KCNQ1OT1, NEAT1, HELLPAR, SNHG16, NUTM2B-AS1, MALAT1, PSMA3-AS1, GABPB1-AS1, NORAD, NKILA) and 4 miRNA (mir-145, mir-223, mir-let-7a, mir-132) as top gene hubs with 4 transcription factors (NFKB1, RELA, ESR1) as master regulators. Together, these factors are likely to be involved in co-regulatory networks driving a myometrial transformation to generate an estrogen sensitive phenotype. We conclude that lncRNA and miRNA targeting the ESR1 and NFKB pathways play a key role in the initiation of human labor. For the first time we perform an integrative analysis to present a multi-level genomic signature in the myometrium for spontaneous term labor.
2022-02-13 | GSE186763 | GEO
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. Keywords: myometrial gene expression, preterm versus term labor
2008-09-27 | GSE9159 | GEO
Project description:Circulating progesterone (P4) levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is functional withdrawal of P4 action at the myometrial level prior to labor onset. Mifepristone is widely used to induce human labour In this study, we aimed to establish and validate a model of human myometrial explants for the study of P4 action. Myometrial biopsies obtained at Caesearean section at term were dissected into explants after a portion was immediately snap-frozen (t=0). Transcriptomic comparison of paired explants and primary myometrial cells as well as the hTert immortalized myometrial cell line demonstrated that explants more closely resemble t=0.
2016-05-30 | GSE77830 | GEO
Project description:Circulating progesterone (P4) levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is functional withdrawal of P4 action at the myometrial level prior to labor onset. Mifepristone is widely used to induce human labour In this study, we aimed to establish and validate a model of human myometrial explants for the study of P4 action. Myometrial biopsies obtained at Caesearean section at term were dissected into explants after a portion was immediately snap-frozen (t=0). Transcriptomic comparison of paired explants and primary myometrial cells as well as the hTert immortalized myometrial cell line demonstrated that explants more closely resemble t=0. Biopsies obtained from non-laboring women at elective Caesarean section at term were divided into 3: (i) dissected and immediately snap-frozen (t=0), (ii) dissected into 3x3x3mm3myometrial explants and (iii) processed for primary cell culture. Explants, primary cells at passage 4 (the typical passage our group uses for experiments) and hTERT cells were cultured for a period of 30 hours without treatment. Total RNA was extracted and microarray analysis performed. 6 replicates were used for this study.
2016-05-30 | E-GEOD-77830 | biostudies-arrayexpress
Project description:Myometrial biopsies were collected from 31 women undergoing primary cesarean sections and were carefully phenotyped with respect to gestational age (GA), circumstances of labor onset, and clinical status at the start and end of the intervention. Cases were aggregated into groups as follows: Group 1: term birth following spontaneous onset of term labor (TL, n=5); Group 2: term birth by elective cesarean section not in labor (TNL, n=5); Group 3: PTB following spontaneous preterm labor with intact membranes (n=6); Group 4: preterm birth following PPROM (n=8); and Group 5: provider-initiated preterm birth in the absence of active labor contractions, cervical dilation or membrane rupture (n=7). Additional phenotyping of cases spontaneously committed to PTBs (Groups 3 and 4) involved presence or absence of Triple I based on cultures of amniotic fluid obtained via clinically-indicated amniocentesis. RNAs were profiled using second generation RNA sequencing.
2021-07-20 | GSE163773 | GEO
Project description:Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation
| PRJNA587064 | ENA
Project description:Myometrial biopsies were collected from 20 women undergoing primary cesarean sections in well-characterized clinical scenarios: 1) term labor of spontaneous onset (TL, n=5); 2) term non-labor (TNL, n=5); 3) spontaneous PTB in the setting of chorioamnionitis (PTB-HCA) and 4) indicated preterm birth (PTB) non-labor (PTB-NL, n=5). RNAs were profiled using 2nd-generation RNA sequencing.
2018-06-14 | GSE99853 | GEO
Project description:Preterm birth is multifactorial in origin with several distinct clinical phenotypes of differing etiologies, including idiopathic preterm birth. Preterm birth involves the interaction of genetic, societal and environmental factors such as nutrition, lifestyle and stress that may modulate the length of gestation via the epigenome. DNA methylation is a well-studied epigenetic modification whereby promoter methylation commonly represses gene expression and vice versa. Myometrial tissue was obtained at cesarean section at term with or without labor, preterm without labor, idiopathic preterm labor, and twin gestations with labor. Differences in the myometrial epigenomes were identified at gene promoters, CpG islands, CpG island shores and shelves, gene bodies across the genome between the groups of women with preterm labor of different phenotypes vs. normal term labor. Functional clustering analysis indicated the significantly enriched pathways of hypomethylated genes (permissive) were related to acute inflammatory and acute-phase responses. By contrast, genes that are hypermethylated (repressive) revealed enrichment for contractile fibers and cell. This study provides the first high-resolution DNA methylome of human myometrium with evidence for differences in the methylome that may relate to idiopathic preterm birth via regulation of gene expression. The findings extend previous observations that idiopathic preterm labor is associated with subclinical intrauterine infection and inflammatory pathways and point to targets for further molecular characterization of preterm delivery. Comparison of the human myometrial epigenomes in pregnancies with preterm labor of different phenotypes vs. normal term labor
2017-05-04 | E-GEOD-71123 | biostudies-arrayexpress
Project description:We compared gene expression profiles in uterus before and after onset of labor. Gene expression profiles were compared between functionally distinct areas of the human uterus: the fundus, lower segment and the cervix in samples obtained before labor and during labor.
2005-04-01 | E-MEXP-106 | biostudies-arrayexpress
Project description:Myometrial transcriptional signatures at spontaneous human term labor (TL) and at term not in labor (TNL)
| PRJNA740331 | ENA