Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia.
Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia.
复制标题
PGR-B和ESR1信号传导的破坏是与严重的先兆子痫有关的有缺陷的c骨化。
DOI：
10.7554/elife.70753
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发表时间：
2021-10-28
期刊：
影响因子：
7.7
通讯作者：
Simon C
中科院分区：
文献类型：
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作者：
Garrido-Gomez T;Castillo-Marco N;Clemente-Ciscar M;Cordero T;Muñoz-Blat I;Amadoz A;Jimenez-Almazan J;Monfort-Ortiz R;Climent R;Perales-Marin A;Simon C
子宫黏膜的脱个体化促使母体适应胎盘的侵袭。需要适当的胎盘浸润深度来支持健康的妊娠；浅侵与严重子痫前期（sPE）的发展有关。母亲通过失败的去个体化对sPE的贡献是胎盘表型的重要决定因素。然而，将脱个体化与sPE联系起来的体内缺陷的分子机制尚不清楚。采用全局RNA测序技术，对既往妊娠中患有sPE的未怀孕妇女和未患sPE的妇女的子宫内膜活检标本进行转录组学分析。样本随机分为两个队列，训练组和测试组，以确定sPE中指纹编码缺陷的去个体化及其后续验证。基因本体富集和相互作用网络加深了sPE中基因失调受损的途径。最后，从基因表达水平和蛋白丰度水平评估脱个体化的主要调节因子雌激素受体1 （ESR1）和孕激素受体B （PGR-B）。在这里，我们发现了编码这种脱个体化缺陷的足迹，包括120个基因-使用在以前怀孕中发生sPE的妇女蜕膜的全球基因表达谱。这种特征使我们能够有效地将样品分为sPE组和对照组。ESR1和PGR与缺陷去个性化指纹的动态网络高度互联。ESR1和PGR-B基因表达和蛋白丰度在sPE中明显中断。因此，去个体化受损的转录组特征暗示了sPE患者子宫内膜中激素信号的失调。这些发现揭示了一个潜在的足迹，可以用于孕前或早期产前筛查sPE风险，从而改善预防和早期治疗。这项工作得到了西班牙卡洛斯三世研究所授予TGG的PI19/01659 （MCIU/AEI/FEDER， UE）的资助。NCM得到了西班牙巴伦西亚政府FDGENT/2019/008博士项目的支持。IMB由博士项目PRE2019-090770支持，由西班牙科学与创新部RTI2018-094946-B-100 （MCIU/AEI/FEDER， UE）资助，CS担任首席研究员。这项研究部分由Igenomix S.L.资助
Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlying the in vivo defect linking decidualization to sPE is unknown. Global RNA sequencing was applied to obtain the transcriptomic profile of endometrial biopsies collected from nonpregnant women who suffer sPE in a previous pregnancy and women who did not develop this condition. Samples were randomized in two cohorts, the training and the test set, to identify the fingerprinting encoding defective decidualization in sPE and its subsequent validation. Gene Ontology enrichment and an interaction network were performed to deepen in pathways impaired by genetic dysregulation in sPE. Finally, the main modulators of decidualization, estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B), were assessed at the level of gene expression and protein abundance. Here, we discover the footprint encoding this decidualization defect comprising 120 genes—using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. ESR1 and PGR were highly interconnected with the dynamic network of the defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE. Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that could be leveraged for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments. This work has been supported by the grant PI19/01659 (MCIU/AEI/FEDER, UE) from the Spanish Carlos III Institute awarded to TGG. NCM was supported by the PhD program FDGENT/2019/008 from the Spanish Generalitat Valenciana. IMB was supported by the PhD program PRE2019-090770 and funding was provided by the grant RTI2018-094946-B-100 (MCIU/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation with CS as principal investigator. This research was funded partially by Igenomix S.L.