Transcriptomic analysis reveals myometrial topologically associated domains linked to the onset of human term labour

Abstract

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 allocate 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 RNA sequencing (RNAseq) analysis of myometrial samples (n = 16) 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, respectively. 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 15 new lncRNA (MCM3AP-AS1, TUG1, MIR29B2CHG, HCG18, LINC00963, KCNQ1OT1, NEAT1, HELLPAR, SNHG16, NUTM2B-AS1, MALAT1, PSMA3-AS1, GABPB1-AS1, NORAD, NKILA) and four miRNA (mir-145, mir-223, mir-let-7a, mir-132) as top gene hubs with three 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 estrogen receptor 1 and nuclear factor kappa B 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 made of mRNA, ncRNA and transcription factors in the myometrium for spontaneous term labor.

LncRNA PSMA3-AS1 promotes preterm delivery by inducing ferroptosis via miR-224-3p/Nrf2 axis

“…PSMA3-AS1 is also reported to regulate oxidative stress and GSH-Px activities to promote gastric cancer progression (21). Based on the transcriptomic analysis, a previous study has revealed that PSMA3-AS1 is identified as one of the hub genes implicated in co-regulatory networks that drive a myometrial transformation and thus produce an estrogen-sensitive phenotype in pregnant women (22). However, the mechanisms underlying the potential of PSMA3-AS1 in premature delivery…”