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Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term.

ABSTRACT: 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.

SUBMITTER: Mittal P

PROVIDER: S-EPMC3097097 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term.

Mittal Pooja P Romero Roberto R Tarca Adi L AL Gonzalez Juan J Draghici Sorin S Xu Yi Y Dong Zhong Z Nhan-Chang Chia-Ling CL Chaiworapongsa Tinnakorn T Lye Stephen S Kusanovic Juan Pedro JP Lipovich Leonard L Mazaki-Tovi Shali S Hassan Sonia S SS Mesiano Sam S Kim Chong Jai CJ

Journal of perinatal medicine 20100714 6

<h4>Aims</h4>to characterize the transcriptome of human myometrium during spontaneous labor at term.<h4>Methods</h4>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-l ...[more]

PMID: 20629487

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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: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.

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Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term.

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Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term.

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