Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, University of Manchester, Manchester, UK.
St Mary's Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Biol Reprod. 2018 Mar 1;98(3):422-436. doi: 10.1093/biolre/iox186.
Preterm deliveries remain the leading cause of neonatal morbidity and mortality. Current therapies target only myometrial contractions and are largely ineffective. As labor involves multiple coordinated events across maternal and fetal tissues, identifying fundamental regulatory pathways of normal term labor is vital to understanding successful parturition and consequently labor pathologies. We aimed to identify transcriptomic signatures of human normal term labor of two tissues: in the fetal-facing choriodecidua and the maternal myometrium. Microarray transcriptomic data from choriodecidua and myometrium following term labor were analyzed for functional hierarchical networks, using Cytoscape 2.8.3. Hierarchically high candidates were analyzed for their regulatory casual relationships using Ingenuity Pathway Analysis. Selected master regulators were then chemically inhibited and effects on downstream targets were assessed using real-time quantitative PCR (RT-qPCR). Unbiased network analysis identified upstream molecular components in choriodecidua including vimentin, TLR4, and TNFSF13B. In the myometrium, candidates included metallothionein 2 (MT2A), TLR2, and RELB. These master regulators had significant differential gene expression during labor, hierarchically high centrality in community cluster networks, interactions amongst the labor gene set, and strong causal relationships with multiple downstream effects. In vitro experiments highlighted MT2A as an effective regulator of labor-associated genes. We have identified unique potential regulators of the term labor transcriptome in uterine tissues using a robust sequence of unbiased mathematical and literature-based in silico analyses. These findings encourage further investigation into the efficacy of predicted master regulators in blocking multiple pathways of labor processes across maternal and fetal tissues, and their potential as therapeutic approaches.
早产仍然是新生儿发病率和死亡率的主要原因。目前的治疗方法仅针对子宫收缩，而且效果不大。由于分娩涉及母体和胎儿组织中的多个协调事件，因此确定正常足月分娩的基本调节途径对于理解成功分娩以及随后的分娩病理至关重要。我们旨在确定两种组织（胎儿面的绒毛膜蜕膜和母体的子宫肌层）中人类正常足月分娩的转录组特征。使用 Cytoscape 2.8.3 分析绒毛膜蜕膜和足月分娩后子宫肌层的微阵列转录组数据的功能层次网络。使用Ingenuity Pathway Analysis 分析分层候选物的调节因果关系。然后用化学抑制剂抑制选定的主调节因子，并使用实时定量 PCR（RT-qPCR）评估对下游靶标的影响。无偏网络分析确定了绒毛膜蜕膜中的上游分子成分，包括波形蛋白、TLR4 和 TNFSF13B。在子宫肌层中，候选物包括金属硫蛋白 2（MT2A）、TLR2 和 RELB。这些主调节因子在分娩过程中具有显著的差异基因表达，在社区聚类网络中具有较高的层次中心性，与分娩基因集相互作用，并且与多个下游效应具有很强的因果关系。体外实验突出了 MT2A 作为与分娩相关基因的有效调节剂。我们使用一系列强大的无偏数学和基于文献的计算分析方法，在子宫组织中鉴定了独特的足月分娩转录组潜在调节因子。这些发现鼓励进一步研究预测的主调节因子在阻断母体和胎儿组织中多个分娩过程途径的功效，以及它们作为治疗方法的潜力。
