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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 5

The expression ratio of 2 anticorrelated calcium transporter genes reliably distinguishes myometrial quiescence from the nonquiescent phenotype.

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The expression ratio of 2 anticorrelated calcium transporter genes relia...
(A) Box and whisker plots (box, median with IQR; whiskers, inner fences using Tukey’s method) showing expression ratios of transcripts encoding ATP2B4 and ATP2B2 as determined by RNA-seq (Q, quiescent phenotype, n = 22; NQ, nonquiescent phenotype, n = 9). Asterisk indicates statistical significance (P < 0.001, Mann-Whitney U test). (B) Box and whisker plots (as in A) showing qPCR expression ratios of ATP2B4/ATP2B2, stratified by phenotype (Q, n = 27; NQ, n = 15). Asterisk indicates statistical significance (P < 0.001, Mann-Whitney U test). (C) Scatterplot showing the extent of correlation between ATP2B4/ATP2B2 expression ratios determined using RNA-seq and qPCR in 31 samples (r = 0.76, P < 0.001). TNL specimens are indicated by blue circles, TL samples are indicated by red squares, and preterm NQ and Q specimens are depicted by light red and light blue triangles, respectively. (D) ROC curve analysis applied to binary classification of NQ and Q specimens based on expression ratios of ATP2B4/ATP2B2 calculated either by qPCR (for samples from the current study) or RNA-seq (for samples from the current study, samples from prior published studies [GSE50599, n = 10; and GSE80172, n = 22], and an integrated data set comprising samples from the current study and the 2 existing data sets). All AUC values achieved statistical significance (P < 0.001). (E) Relative abundances of transcripts with expression highly correlated (r ≥ 0.95) with ATP2B4 (233 transcripts, green) or ATP2A2 (121 transcripts, purple). TNL specimens are indicated by blue circles, TL samples are indicated by red squares, and preterm NQ and Q specimens are depicted by light red and light blue triangles, respectively. (F) Overrepresented pathways for transcripts in E, plotted by average log10-scaled baseline expression in Q (term and preterm) specimens, and projection of transcript along PC1 in principle component analysis.

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