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Molecular signatures of labor and nonlabor myometrium with parsimonious classification from 2 calcium transporter genes
William E. Ackerman IV, … , Guomao Zhao, Irina A. Buhimschi
William E. Ackerman IV, … , Guomao Zhao, Irina A. Buhimschi
Published May 4, 2021
Citation Information: JCI Insight. 2021;6(11):e148425. https://doi.org/10.1172/jci.insight.148425.
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Research Article Reproductive biology

Molecular signatures of labor and nonlabor myometrium with parsimonious classification from 2 calcium transporter genes

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Abstract

Clinical phenotyping of term and preterm labor is imprecise, and disagreement persists on categorization relative to underlying pathobiology, which remains poorly understood. We performed RNA sequencing (RNA-seq) of 31 specimens of human uterine myometrium from 10 term and 21 preterm cesarean deliveries with rich clinical context information. A molecular signature of 4814 transcripts stratified myometrial samples into quiescent (Q) and nonquiescent (NQ) phenotypes, independent of gestational age and incision site. Similar stratifications were achieved using expressed genes in Ca2+ signaling and TGF-β pathways. For maximal parsimony, we evaluated the expression of just 2 Ca2+ transporter genes, ATP2B4 (encoding PMCA4) and ATP2A2 (coding for SERCA2), and we found that their ratio reliably distinguished NQ and Q specimens in the current study, and also in 2 publicly available RNA-seq data sets (GSE50599 and GSE80172), with an overall AUC of 0.94. Cross-validation of the ATP2B4/ATP2A2 ratio by quantitative PCR in an expanded cohort (by 11 additional specimens) achieved complete separation (AUC of 1.00) of NQ versus Q specimens. While providing additional insight into the associations between clinical features of term and preterm labor and myometrial gene expression, our study also offers a practical algorithm for unbiased classification of myometrial biopsies by their overall contractile program.

Authors

William E. Ackerman IV, Catalin S. Buhimschi, Ali Snedden, Taryn L. Summerfield, Guomao Zhao, Irina A. Buhimschi

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Figure 3

Characteristics of the transcriptional landscape differentiating the quiescent (Q) and nonquiescent (NQ) molecular phenotypes.

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Characteristics of the transcriptional landscape differentiating the qui...
Enrichment map of gene sets exhibiting significant enrichment by the GSEA algorithm (P < 0.005, FDR < 0.1) based on the transcriptional expression signature in myometrial samples. Markov cluster analysis was used to identify 9 dense subclusters within the network, indicated by the labeled ellipses. Within the network diagram, node size reflects the number of genes in each enriched set, node color indicates the direction of enrichment, and edges represent the overlap coefficient between adjacent nodes as a similarity metric. The blue arrow indicates the KEGG calcium signaling pathway within a subnetwork enriched for Ca2+ binding and Ca2+ transport genes.

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