PMID- 34709177 OWN - NLM STAT- MEDLINE DCOM- 20211119 LR - 20211203 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 10 DP - 2021 Oct 28 TI - Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia. LID - 10.7554/eLife.70753 [doi] LID - e70753 AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FUNDING: 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. CI - (c) 2021, Garrido-Gomez et al. FAU - Garrido-Gomez, Tamara AU - Garrido-Gomez T AUID- ORCID: 0000-0002-6584-4832 AD - Igenomix Foundation, INCLIVA, Valencia, Spain. FAU - Castillo-Marco, Nerea AU - Castillo-Marco N AUID- ORCID: 0000-0002-4817-4777 AD - Igenomix Foundation, INCLIVA, Valencia, Spain. FAU - Clemente-Ciscar, Monica AU - Clemente-Ciscar M AD - Igenomix, Valencia, Spain. FAU - Cordero, Teresa AU - Cordero T AD - Igenomix Foundation, INCLIVA, Valencia, Spain. FAU - Munoz-Blat, Irene AU - Munoz-Blat I AD - Igenomix Foundation, INCLIVA, Valencia, Spain. FAU - Amadoz, Alicia AU - Amadoz A AUID- ORCID: 0000-0003-3915-0404 AD - Igenomix, Valencia, Spain. FAU - Jimenez-Almazan, Jorge AU - Jimenez-Almazan J AD - Igenomix, Valencia, Spain. FAU - Monfort-Ortiz, Rogelio AU - Monfort-Ortiz R AUID- ORCID: 0000-0001-7931-8609 AD - Department of Obstetrics and Gynecology, University and Polytechnic La Fe Hospital, Valencia, Spain. FAU - Climent, Reyes AU - Climent R AD - Department of Obstetrics and Gynecology, University and Polytechnic La Fe Hospital, Valencia, Spain. FAU - Perales-Marin, Alfredo AU - Perales-Marin A AUID- ORCID: 0000-0002-2221-2560 AD - Department of Obstetrics and Gynecology, University and Polytechnic La Fe Hospital, Valencia, Spain. AD - Department of Obstetrics and Gynecology, School of Medicine, Valencia University, Valencia, Spain. FAU - Simon, Carlos AU - Simon C AD - Igenomix Foundation, INCLIVA, Valencia, Spain. AD - Department of Obstetrics and Gynecology, School of Medicine, Valencia University, Valencia, Spain. AD - Obstetrics & Gynecology, BIDMC Harvard University, Boston, United States. LA - eng SI - GEO/GSE172381 SI - GEO/GSE94644 SI - GEO/GSE111976 SI - GEO/GSE23072 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211028 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (ESR1 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (Receptors, Progesterone) RN - 0 (progesterone receptor B) SB - IM MH - Adult MH - Decidua/metabolism/*pathology MH - Estrogen Receptor alpha/*genetics/metabolism MH - Female MH - Gene Expression Profiling MH - Humans MH - Pre-Eclampsia/*genetics/metabolism MH - Pregnancy MH - Receptors, Progesterone/*genetics/metabolism MH - *Signal Transduction MH - Young Adult PMC - PMC8553341 OTO - NOTNLM OT - Preeclampsia OT - chromosomes OT - decidua OT - defective decidualization OT - gene expression OT - hormonal receptor OT - human OT - human endometrium OT - medicine OT - transcriptomic fingerprint COIS- TG, NC, MC, TC, IM, AA, JJ, RM, RC, AP, CS No competing interests declared EDAT- 2021/10/29 06:00 MHDA- 2021/11/20 06:00 PMCR- 2021/10/28 CRDT- 2021/10/28 12:21 PHST- 2021/05/27 00:00 [received] PHST- 2021/09/23 00:00 [accepted] PHST- 2021/10/28 12:21 [entrez] PHST- 2021/10/29 06:00 [pubmed] PHST- 2021/11/20 06:00 [medline] PHST- 2021/10/28 00:00 [pmc-release] AID - 70753 [pii] AID - 10.7554/eLife.70753 [doi] PST - epublish SO - Elife. 2021 Oct 28;10:e70753. doi: 10.7554/eLife.70753.