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Characterization of the Myometrial Transcriptome of Long Non-coding RNA Genes in Human Labor by High-Throughput RNA-seq.

ABSTRACT: The contraction of myometrium is pivotal in expelling the fetus and placenta during labor, but the specific mechanism of myometrium changing from quiescent to a contractile state is still unclear. Previous studies have shown that changes in certain genes or proteins are related to the regulation of myometrial contraction, which are considered to be contraction-associated genes. Long non-coding RNAs (lncRNAs) are increasingly recognized as important molecular players in regulating gene expression and many biological processes, but their roles in the rhythmic contraction of myometrial cells during labor remain to be explored. This study aimed to reveal the differentially expressed lncRNAs in the human myometrium of non-labor (NL, n = 9) and in-labor (IL, n = 9). Furthermore, bioinformatic analysis of lncRNA targeted mRNAs was performed to explore the biological processes and pathway alterations during labor. The results showed a total of 112 significantly differentially expressed lncRNAs between two groups were identified, of which 69 were upregulated and 43 were downregulated in IL group, compared with NL group. In addition, the enrichment analysis of Gene Ontology (GO) and pathways showed that the lncRNAs corresponding targeted mRNAs were associated with mRNA splicing, splicesome, ferroptosis, FGFR and NOTCH signaling pathways. Our study constitutes the first report on investigating the gene expression landscape and regulatory mechanism of lncRNAs within laboring and non-laboring myometrium using RNA sequencing (RNA-seq) and bioinformatic analysis. This study provided high-throughput information on the lncRNA in the myometrium of women in labor and those not in labor, to discover novel lncRNA candidates and potential biological pathways involved in human parturition.

SUBMITTER: Luo Y

PROVIDER: S-EPMC9537226 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Characterization of the Myometrial Transcriptome of Long Non-coding RNA Genes in Human Labor by High-Throughput RNA-seq.

Luo Yihong Y Cui Long L Chen Lina L Wang Lele L Ji Kaiyuan K Liu Huishu H

Reproductive sciences (Thousand Oaks, Calif.) 20220425 10

The contraction of myometrium is pivotal in expelling the fetus and placenta during labor, but the specific mechanism of myometrium changing from quiescent to a contractile state is still unclear. Previous studies have shown that changes in certain genes or proteins are related to the regulation of myometrial contraction, which are considered to be contraction-associated genes. Long non-coding RNAs (lncRNAs) are increasingly recognized as important molecular players in regulating gene expression ...[more]

PMID: 35467262

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Project description:AIMS:to characterize the transcriptome of human myometrium during spontaneous labor at term. METHODS:myometrium was obtained from women with (n=19) and without labor (n=20). Illumina HumanHT-12 microarrays were utilized. Moderated t-tests and false discovery rate adjustment of P-values were applied. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for a select set of differentially expressed genes in a separate set of samples. Enzyme-linked immunosorbent assay and Western blot were utilized to confirm differential protein production in a third sample set. RESULTS:1) Four hundred and seventy-one genes were differentially expressed; 2) gene ontology analysis indicated enrichment of 103 biological processes and 18 molecular functions including: a) inflammatory response; b) cytokine activity; and c) chemokine activity; 3) systems biology pathway analysis using signaling pathway impact analysis indicated six significant pathways: a) cytokine-cytokine receptor interaction; b) Jak-STAT signaling; and c) complement and coagulation cascades; d) NOD-like receptor signaling pathway; e) systemic lupus erythematosus; and f) chemokine signaling pathway; 4) qRT-PCR confirmed over-expression of prostaglandin-endoperoxide synthase-2, heparin binding epidermal growth factor (EGF)-like growth factor, chemokine C-C motif ligand 2 (CCL2/MCP1), leukocyte immunoglobulin-like receptor, subfamily A member 5, interleukin (IL)-8, IL-6, chemokine C-X-C motif ligand 6 (CXCL6/GCP2), nuclear factor of kappa light chain gene enhancer in B-cells inhibitor zeta, suppressor of cytokine signaling 3 (SOCS3) and decreased expression of FK506 binding-protein 5 and aldehyde dehydrogenase in labor; 5) IL-6, CXCL6, CCL2 and SOCS3 protein expression was significantly higher in the term labor group compared to the term not in labor group. CONCLUSIONS:myometrium of women in spontaneous labor at term is characterized by a stereotypic gene expression pattern consistent with over-expression of the inflammatory response and leukocyte chemotaxis. Differential gene expression identified with microarray was confirmed with qRT-PCR using an independent set of samples. This study represents an unbiased description of the biological processes involved in spontaneous labor at term based on transcriptomics.

Project description:OBJECTIVE:The molecular basis of failure to progress in labor is poorly understood. This study was undertaken to characterize the myometrial transcriptome of patients with an arrest of dilatation (AODIL). STUDY DESIGN:Human myometrium was prospectively collected from women in the following groups: (1) spontaneous term labor (TL; n=29) and (2) arrest of dilatation (AODIL; n=14). Gene expression was characterized using Illumina® HumanHT-12 microarrays. A moderated Student's t-test and false discovery rate adjustment were used for analysis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of selected genes was performed in an independent sample set. Pathway analysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). The MetaCore knowledge base was also searched for pathway analysis. RESULTS:(1) Forty-two differentially expressed genes were identified in women with an AODIL; (2) gene ontology analysis indicated enrichment of biological processes, which included regulation of angiogenesis, response to hypoxia, inflammatory response, and chemokine-mediated signaling pathway. Enriched molecular functions included transcription repressor activity, heat shock protein (Hsp) 90 binding, and nitric oxide synthase (NOS) activity; (3) MetaCore analysis identified immune response chemokine (C-C motif) ligand 2 (CCL2) signaling, muscle contraction regulation of endothelial nitric oxide synthase (eNOS) activity in endothelial cells, and triiodothyronine and thyroxine signaling as significantly overrepresented (false discovery rate <0.05); (4) qRT-PCR confirmed the overexpression of Nitric oxide synthase 3 (NOS3); hypoxic ischemic factor 1A (HIF1A); Chemokine (C-C motif) ligand 2 (CCL2); angiopoietin-like 4 (ANGPTL4); ADAM metallopeptidase with thrombospondin type 1, motif 9 (ADAMTS9); G protein-coupled receptor 4 (GPR4); metallothionein 1A (MT1A); MT2A; and selectin E (SELE) in an AODIL. CONCLUSION:The myometrium of women with AODIL has a stereotypic transcriptome profile. This disorder has been associated with a pattern of gene expression involved in muscle contraction, an inflammatory response, and hypoxia. This is the first comprehensive and unbiased examination of the molecular basis of an AODIL.

Project description:Preterm birth is recognized as the primary cause of infant mortality worldwide. Twin pregnancies are significantly more at risk of preterm birth than singleton pregnancies. A greater understanding of why this is and better modes of treatment and prevention are needed. Key to this is determining the differing pathophysiological mechanisms of preterm birth in twins, including the role of the myometrium and premature uterine contraction. We performed RNA sequencing (RNA-Seq) of human myometrium from singleton and twin pregnancies at term (> 37+0 weeks) and preterm (< 37+0 weeks), collected during pre-labour Caesarean Section. RNA-Seq libraries were prepared from polyA-selected RNA and sequenced on the Illumina HiSeq 4000 platform. Differentially expressed genes (DEGs), GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment were conducted using R software. Significance was determined with a false discovery rate-adjusted P value of <0.05. Only 3 DEGs were identified between gestational age-matched singleton and twin myometrium and only 1 DEG identified between singleton term and twin preterm tissues. Comparison of singleton preterm myometrium with twin term myometrium however, revealed 75 down-regulated and 24 up-regulated genes in twin myometrium. This included genes associated with inflammation and immune response, T cell maturation and differentiation and steroid biosynthesis. GO and KEGG enrichment analyses for biologically relevant processes and functions also revealed several terms related to inflammation and immune response, as well as cytokine-cytokine receptor interaction and chemokine receptor signalling. Data indicate that little or no differences exist in the transcriptome of singleton and twin myometrium when matched for gestational age. The significant up- and down-regulation of genes identified between preterm singleton and twin myometrium at term may point to transcriptome changes associated with the chronic levels of uterine stretch in twin pregnancy or genes associated with the myometrium transitioning to labour onset.

Dataset Information

Characterization of the Myometrial Transcriptome of Long Non-coding RNA Genes in Human Labor by High-Throughput RNA-seq.

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Characterization of the Myometrial Transcriptome of Long Non-coding RNA Genes in Human Labor by High-Throughput RNA-seq.

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