Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA.
The High Performance Computing Facility, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Nationwide Children's Hospital, Columbus, Ohio, USA.
JCI Insight. 2021 Jun 8;6(11):148425. doi: 10.1172/jci.insight.148425.
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.
足月和早产临产的临床表型不精确，且相对于潜在的病理生物学分类仍存在分歧，而后者的理解仍很差。我们对 31 个来自 10 例足月和 21 例早产剖宫产的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 Ca2+信号和 TGF-β途径中表达的基因也可以实现类似的分层。为了最大限度地保持简约性，我们仅评估了 2 个 Ca2+转运体基因（ATP2B4（编码 PMCA4）和 ATP2A2（编码 SERCA2）的表达，我们发现它们的比值在本研究中以及在 2 个公开的 RNA-seq 数据集（GSE50599 和 GSE80172）中可靠地区分了 NQ 和 Q 标本，总体 AUC 为 0.94。通过定量 PCR 对 ATP2B4/ATP2A2 比值在扩大队列（另外 11 个标本）中的交叉验证实现了 NQ 与 Q 标本的完全分离（AUC 为 1.00）。虽然本研究为足月和早产临产的临床特征与子宫肌层基因表达之间的相关性提供了更多的见解，但它还为通过整体收缩程序对子宫肌层活检进行无偏分类提供了一种实用的算法。
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