Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia

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 s...

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Autores principales:	Tamara Garrido-Gomez, Nerea Castillo-Marco, Mónica Clemente-Ciscar, Teresa Cordero, Irene Muñoz-Blat, Alicia Amadoz, Jorge Jimenez-Almazan, Rogelio Monfort-Ortiz, Reyes Climent, Alfredo Perales-Marin, Carlos Simon
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	Preeclampsia human endometrium decidua defective decidualization transcriptomic fingerprint hormonal receptor Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/16e7af94886c455dba3d9bf58f47abf0
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spelling	oai:doaj.org-article:16e7af94886c455dba3d9bf58f47abf02021-12-01T12:14:55ZDisrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia10.7554/eLife.707532050-084Xe70753https://doaj.org/article/16e7af94886c455dba3d9bf58f47abf02021-10-01T00:00:00Zhttps://elifesciences.org/articles/70753https://doaj.org/toc/2050-084XBackground: 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.Tamara Garrido-GomezNerea Castillo-MarcoMónica Clemente-CiscarTeresa CorderoIrene Muñoz-BlatAlicia AmadozJorge Jimenez-AlmazanRogelio Monfort-OrtizReyes ClimentAlfredo Perales-MarinCarlos SimoneLife Sciences Publications LtdarticlePreeclampsiahuman endometriumdeciduadefective decidualizationtranscriptomic fingerprinthormonal receptorMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Preeclampsia human endometrium decidua defective decidualization transcriptomic fingerprint hormonal receptor Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	Preeclampsia human endometrium decidua defective decidualization transcriptomic fingerprint hormonal receptor Medicine R Science Q Biology (General) QH301-705.5 Tamara Garrido-Gomez Nerea Castillo-Marco Mónica Clemente-Ciscar Teresa Cordero Irene Muñoz-Blat Alicia Amadoz Jorge Jimenez-Almazan Rogelio Monfort-Ortiz Reyes Climent Alfredo Perales-Marin Carlos Simon Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia
description	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.
format	article
author	Tamara Garrido-Gomez Nerea Castillo-Marco Mónica Clemente-Ciscar Teresa Cordero Irene Muñoz-Blat Alicia Amadoz Jorge Jimenez-Almazan Rogelio Monfort-Ortiz Reyes Climent Alfredo Perales-Marin Carlos Simon
author_facet	Tamara Garrido-Gomez Nerea Castillo-Marco Mónica Clemente-Ciscar Teresa Cordero Irene Muñoz-Blat Alicia Amadoz Jorge Jimenez-Almazan Rogelio Monfort-Ortiz Reyes Climent Alfredo Perales-Marin Carlos Simon
author_sort	Tamara Garrido-Gomez
title	Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia
title_short	Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia
title_full	Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia
title_fullStr	Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia
title_full_unstemmed	Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia
title_sort	disrupted pgr-b and esr1 signaling underlies defective decidualization linked to severe preeclampsia
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/16e7af94886c455dba3d9bf58f47abf0
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Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia

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