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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 4

Myometrial nonquiescence is associated with potential dysregulation of Ca2+ signaling and TGF-β pathways.

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Myometrial nonquiescence is associated with potential dysregulation of C...
(A) Gene set enrichment plot for the 183 transcripts related to the KEGG calcium signaling pathway. For this analysis, gene expression ranking in the TL versus TNL comparison was done by the adjusted P value (FDR) as determined using the DESeq2 algorithm, and statistical enrichment for the gene set was determined using 1000 gene list permutations. (B) Scatterplot of the top 2 principal components following dimensionality reduction of differentially abundant calcium signaling transcripts. TNL specimens are indicated by blue circles, TL samples are indicated by red squares, and preterm NQ (nonquiescent phenotype) and Q (quiescent phenotype) specimens are depicted by light red and light blue triangles, respectively. (C) Heatmap of average, log2-transformed, normalized RNA-seq feature counts for the 68 calcium signaling transcripts exhibiting significant differences in abundance between the TL and TNL myometrial samples (FDR < 0.1, fold-change of at least ± 1.5). Asterisks denote the 2 mRNAs encoding calcium transporter proteins selected for more detailed analysis: ATP2B4 and ATP2A2. Note that a difference between 2 values, a – b, in the log2-transformed data corresponds to a linear difference of 2a – 2b. (D) Gene set enrichment plot for the 84 transcripts related to the TGF-β signaling KEGG pathway, conducted as described above. (E) Scatterplot of the dominant principal components following PCA applied to differentially abundant TGF-β pathway transcripts. Sample annotation is equivalent to that in B. (F) Heatmap of the average normalized RNA-seq feature counts (log2-scaled) for the 23 TGF-β pathway genes that differed significantly between the TL and TNL myometrial samples (FDR < 0.1, minimum fold-change ± 1.5).

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