Molecular signatures of labor and nonlabor myometrium with parsimonious classification from 2 calcium transporter genes
Molecular signatures of labor and nonlabor myometrium with parsimonious classification from 2 calcium transporter genes
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DOI：
10.1172/jci.insight.148425
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发表时间：
2021-06-08
期刊：
影响因子：
8
通讯作者：
Buhimschi, Irina A.
中科院分区：
文献类型：
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作者：
Ackerman, William E.;Buhimschi, Catalin S.;Buhimschi, Irina A.
足月分娩和早产的临床表型是不精确的，并且在相对于基础病理学的分类上存在分歧，这仍然知之甚少。我们对来自10例足月和21例早产剖宫产分娩的31例人子宫肌层标本进行了RNA测序（RNA-seq），这些标本具有丰富的临床背景信息。4814个转录本的分子特征将子宫肌层样本分为静止（Q）和非静止（NQ）表型，与胎龄和切口部位无关。使用Ca 2+信号传导和TGF-β途径中的表达基因实现了类似的分层。为了最大限度地节约，我们仅评估了2种Ca 2+转运蛋白基因ATP 2B 4（编码PMCA 4）和ATP 2A 2（编码SERCA 2）的表达，我们发现它们的比率可靠地区分了当前研究中的NQ和Q标本，以及2个公开可用的RNA-seq数据集（GSE 50599和GSE 80172），总体AUC为0.94。在扩展队列（通过11份额外标本）中通过定量PCR对ATP 2B 4/ATP 2A 2比值进行交叉验证，实现了NQ与Q标本的完全分离（AUC为1.00）。我们的研究提供了关于足月分娩和早产临床特征与子宫肌层基因表达之间关系的更多信息，同时也提供了一种实用的算法，用于根据子宫肌层活检的总体收缩程序进行无偏分类。
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-beta 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.