Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance Between STOX1 Isoforms

Overview

Journal iScience

Publisher Cell Press

Date 2020 May 7

PMID 32371375

Citations 13

Authors

Aurelien Ducat

Betty Couderc

Anthony Bouter

Louise Biquard

Rajaa Aouache

Bruno Passet

Ludivine Doridot

Marie-Benoite Cohen

Pascale Ribaux

Clara Apicella

Irene Gaillard

Sophia Palfray

Yulian Chen

Alexandra Vargas

Amelie Jule

Leo Frelin

Julie Cocquet

Camino Ruano San Martin

Sebastien Jacques

Florence Busato

Jorg Tost

Celine Mehats

Paul Laissue

Jean-Luc Vilotte

Francisco Miralles

Daniel Vaiman

Affiliations

Soon will be listed here.

Abstract

STOX1 is a transcription factor involved in preeclampsia and Alzheimer disease. We show that the knock-down of the gene induces rather mild effect on gene expression in trophoblast cell lines (BeWo). We identified binding sites of STOX1 shared by the two major isoforms, STOX1A and STOX1B. Profiling gene expression of cells overexpressing either STOX1A or STOX1B, we identified genes downregulated by both isoforms, with a STOX1 binding site in their promoters. Among those, STOX1-induced Annexin A1 downregulation led to abolished membrane repair in BeWo cells. By contrast, overexpression of STOX1A or B has opposite effects on trophoblast fusion (acceleration and inhibition, respectively) accompanied by syncytin genes deregulation. Also, STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress. In sum, our work shows that STOX1 isoform imbalance is a cause of gene expression deregulation in the trophoblast, possibly leading to placental dysfunction and preeclampsia.

Citing Articles

Linking genotype to trophoblast phenotype in preeclampsia and HELLP syndrome associated with genetic variants.

Costa L, Bermudez-Guzman L, Benouda I, Laissue P, Morel A, Jimenez K iScience. 2024; 27(3):109260.

PMID: 38439971 PMC: 10910284. DOI: 10.1016/j.isci.2024.109260.

Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines.

Sammar M, Apicella C, Altevogt P, Meiri H, Vaiman D Int J Mol Sci. 2022; 23(24).

PMID: 36555567 PMC: 9783292. DOI: 10.3390/ijms232415927.

Transcriptomic analysis of the human placenta reveals trophoblast dysfunction and augmented Wnt signalling associated with spontaneous preterm birth.

Akram K, Kulkarni N, Brook A, Wyles M, Anumba D Front Cell Dev Biol. 2022; 10:987740.

PMID: 36353514 PMC: 9638416. DOI: 10.3389/fcell.2022.987740.

Modeling placental development and disease using human pluripotent stem cells.

Morey R, Bui T, Fisch K, Horii M Placenta. 2022; 141:18-25.

PMID: 36333266 PMC: 10148925. DOI: 10.1016/j.placenta.2022.10.011.

How trophoblasts fuse: an in-depth look into placental syncytiotrophoblast formation.

Renaud S, Jeyarajah M Cell Mol Life Sci. 2022; 79(8):433.

PMID: 35859055 PMC: 11072895. DOI: 10.1007/s00018-022-04475-z.

References

Tyberghein K, Goossens S, Haigh J, VAN Roy F, van Hengel J . Tissue-wide overexpression of alpha-T-catenin results in aberrant trophoblast invasion but does not cause embryonic mortality in mice. Placenta. 2012; 33(7):554-60. DOI: 10.1016/j.placenta.2012.04.002. View

Kita Y, Nishiyama M, Nakayama K . Identification of CHD7S as a novel splicing variant of CHD7 with functions similar and antagonistic to those of the full-length CHD7L. Genes Cells. 2012; 17(7):536-47. DOI: 10.1111/j.1365-2443.2012.01606.x. View

Chirn G, Rahman R, Sytnikova Y, Matts J, Zeng M, Gerlach D . Conserved piRNA Expression from a Distinct Set of piRNA Cluster Loci in Eutherian Mammals. PLoS Genet. 2015; 11(11):e1005652. PMC: 4654475. DOI: 10.1371/journal.pgen.1005652. View

Zhang C, Ji Z, Wang M, Zhang W, Yang R, An H . Stox1 as a novel transcriptional suppressor of Math1 during cerebellar granule neurogenesis and medulloblastoma formation. Cell Death Differ. 2016; 23(12):2042-2053. PMC: 5136492. DOI: 10.1038/cdd.2016.85. View

van Abel D, Abdulhamid O, Scheper W, van Dijk M, Oudejans C . STOX1A induces phosphorylation of tau proteins at epitopes hyperphosphorylated in Alzheimer's disease. Neurosci Lett. 2012; 528(2):104-9. DOI: 10.1016/j.neulet.2012.09.017. View

Amaral L, Pinheiro L, Guimaraes D, Palei A, Sertorio J, Portella R . Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre-eclampsia. J Cell Mol Med. 2013; 17(10):1300-7. PMC: 4159028. DOI: 10.1111/jcmm.12106. View

Turco M, Gardner L, Kay R, Hamilton R, Prater M, Hollinshead M . Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature. 2018; 564(7735):263-267. PMC: 7220805. DOI: 10.1038/s41586-018-0753-3. View

Chen J, Sheehan P, Brennecke S, Keogh R . Vessel remodelling, pregnancy hormones and extravillous trophoblast function. Mol Cell Endocrinol. 2011; 349(2):138-44. DOI: 10.1016/j.mce.2011.10.014. View

Carbillon L, Challier J, Alouini S, Uzan M, Uzan S . Uteroplacental circulation development: Doppler assessment and clinical importance. Placenta. 2001; 22(10):795-9. DOI: 10.1053/plac.2001.0732. View

10.

Ruttkay-Nedecky B, Nejdl L, Gumulec J, Zitka O, Masarik M, Eckschlager T . The role of metallothionein in oxidative stress. Int J Mol Sci. 2013; 14(3):6044-66. PMC: 3634463. DOI: 10.3390/ijms14036044. View

11.

Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank P, Casimiro M . Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": a transcriptional informatics analysis with validation. Cell Cycle. 2010; 9(11):2201-19. DOI: 10.4161/cc.9.11.11848. View

12.

Szklarczyk D, Gable A, Lyon D, Junge A, Wyder S, Huerta-Cepas J . STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2018; 47(D1):D607-D613. PMC: 6323986. DOI: 10.1093/nar/gky1131. View

13.

van Dijk M, van Bezu J, van Abel D, Dunk C, Blankenstein M, Oudejans C . The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation. Hum Mol Genet. 2010; 19(13):2658-67. DOI: 10.1093/hmg/ddq152. View

14.

Lennon N, Kho A, Bacskai B, Perlmutter S, Hyman B, Brown Jr R . Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J Biol Chem. 2003; 278(50):50466-73. DOI: 10.1074/jbc.M307247200. View

15.

Perez-Sanchez C, de La Fuente C, Granadino B, Velasco G, Rey-Campos J . FHX, a novel fork head factor with a dual DNA binding specificity. J Biol Chem. 2000; 275(17):12909-16. DOI: 10.1074/jbc.275.17.12909. View

16.

Pantham P, Rosario R, Chen Q, Print C, Chamley L . Transcriptomic analysis of placenta affected by antiphospholipid antibodies: following the TRAIL of trophoblast death. J Reprod Immunol. 2012; 94(2):151-4. DOI: 10.1016/j.jri.2012.03.487. View

17.

Ducat A, Doridot L, Calicchio R, Mehats C, Vilotte J, Castille J . Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia. Sci Rep. 2016; 6:19196. PMC: 4725931. DOI: 10.1038/srep19196. View

18.

Nie X, Zhang K, Wang L, Ou G, Zhu H, Gao W . Transcription factor STOX1 regulates proliferation of inner ear epithelial cells via the AKT pathway. Cell Prolif. 2015; 48(2):209-20. PMC: 6495863. DOI: 10.1111/cpr.12174. View

19.

Shankar K, Kang P, Zhong Y, Borengasser S, Wingfield C, Saben J . Transcriptomic and epigenomic landscapes during cell fusion in BeWo trophoblast cells. Placenta. 2015; 36(12):1342-51. DOI: 10.1016/j.placenta.2015.10.010. View

20.

Azar C, Valentine M, Trausch-Azar J, Druley T, Nelson D, Schwartz A . RNA-Seq identifies genes whose proteins are transformative in the differentiation of cytotrophoblast to syncytiotrophoblast, in human primary villous and BeWo trophoblasts. Sci Rep. 2018; 8(1):5142. PMC: 5865118. DOI: 10.1038/s41598-018-23379-2. View