Unveiling the Molecular Mechanisms of Recurrent Miscarriage Through Endoplasmic Reticulum Stress Related Gene Expression

Overview

Journal Sci Rep

Date 2025 Jan 9

PMID 39789034

Authors

Xiaodan Yin

Wei Yang

Mingwei Xin

Qian Han

Siqi Guan

Junqin He

Affiliations

Soon will be listed here.

Abstract

Recurrent miscarriage (RM) is a reproductive disorder affecting couples worldwide. The underlying molecular mechanisms remain elusive, even though emerging evidence has implicated endoplasmic reticulum stress (ERS). We investigated RM- and ERS-related genes to develop a diagnostic model that can enhance predictive ability. We utilized the R package GEO query to extract and process Gene Expression Omnibus data, applying batch correction, normalization, and differential gene expression analysis with limma. ERS-related differentially expressed genes (ERSRGs) were identified through Gene Ontology and Kyoto Encyclopedia of genes and genomes analyses, and their diagnostic potential was assessed. Diagnostic models were developed using logistic regression, support vector machines, and least absolute shrinkage and selection operators, complemented by immune infiltration analysis and regulatory network construction. Integrated analysis revealed 1395 differentially expressed genes (DEGs), including 626 upregulated and 769 downregulated genes. Seventeen ERSRGs were identified. KEAP1 and YIPF5 displayed high diagnostic accuracy (area under the curve [AUC] > 0.9). Gene Ontology and Kyoto Encyclopedia of genes and genomes analyses highlighted the role of ESRDEGs in cellular responses to ERS, protein processing, and apoptosis. Diagnostic models demonstrated robust predictive performance (AUC > 0.9). A molecular interaction was found between RM and the ERS response, and the identified ESRDEGs could serve as potential biomarkers for diagnosis.

References

Rull K, Tomberg K, Koks S, Mannik J, Mols M, Sirotkina M . Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage. Placenta. 2013; 34(2):141-8. PMC: 3562443. DOI: 10.1016/j.placenta.2012.11.032. View

Shen Y, Cao Y, Zhou L, Wu J, Mao M . Construction of an endoplasmic reticulum stress-related gene model for predicting prognosis and immune features in kidney renal clear cell carcinoma. Front Mol Biosci. 2022; 9:928006. PMC: 9478755. DOI: 10.3389/fmolb.2022.928006. View

Wang X, Sun Z, Villeneuve N, Zhang S, Zhao F, Li Y . Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008; 29(6):1235-43. PMC: 3312612. DOI: 10.1093/carcin/bgn095. View

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

Jung E, An B, Choi K, Jeung E . Apoptosis- and endoplasmic reticulum stress-related genes were regulated by estrogen and progesterone in the uteri of calbindin-D(9k) and -D(28k) knockout mice. J Cell Biochem. 2011; 113(1):194-203. DOI: 10.1002/jcb.23344. View

Zhou K, Liu S, Sun W, Zheng L, Zhou H, Yang J . ChIPBase v2.0: decoding transcriptional regulatory networks of non-coding RNAs and protein-coding genes from ChIP-seq data. Nucleic Acids Res. 2016; 45(D1):D43-D50. PMC: 5210649. DOI: 10.1093/nar/gkw965. View

Kolte A, Bernardi L, Christiansen O, Quenby S, Farquharson R, Goddijn M . Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2014; 30(3):495-8. DOI: 10.1093/humrep/deu299. View

Sanz H, Valim C, Vegas E, Oller J, Reverter F . SVM-RFE: selection and visualization of the most relevant features through non-linear kernels. BMC Bioinformatics. 2018; 19(1):432. PMC: 6245920. DOI: 10.1186/s12859-018-2451-4. View

Hanzelmann S, Castelo R, Guinney J . GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14:7. PMC: 3618321. DOI: 10.1186/1471-2105-14-7. View

10.

Haze K, Yoshida H, Yanagi H, Yura T, Mori K . Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999; 10(11):3787-99. PMC: 25679. DOI: 10.1091/mbc.10.11.3787. View

11.

Randhawa V, Kumar M . An integrated network analysis approach to identify potential key genes, transcription factors, and microRNAs regulating human hematopoietic stem cell aging. Mol Omics. 2021; 17(6):967-984. DOI: 10.1039/d1mo00199j. View

12.

Mi H, Muruganujan A, Ebert D, Huang X, Thomas P . PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2018; 47(D1):D419-D426. PMC: 6323939. DOI: 10.1093/nar/gky1038. View

13.

Oakes S, Papa F . The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2014; 10:173-94. PMC: 5568783. DOI: 10.1146/annurev-pathol-012513-104649. View

14.

Szegezdi E, Logue S, Gorman A, Samali A . Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006; 7(9):880-5. PMC: 1559676. DOI: 10.1038/sj.embor.7400779. View

15.

Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View

16.

Zhang H, Zhu Y, Suehiro Y, Mitani S, Xue D . AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations. Proc Natl Acad Sci U S A. 2023; 120(36):e2302490120. PMC: 10483642. DOI: 10.1073/pnas.2302490120. View

17.

Boyce M, Bryant K, Jousse C, Long K, Harding H, Scheuner D . A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005; 307(5711):935-9. DOI: 10.1126/science.1101902. View

18.

Gangwar I, Sharma N, Panzade G, Awasthi S, Agrawal A, Shankar R . Detecting the Molecular System Signatures of Idiopathic Pulmonary Fibrosis through Integrated Genomic Analysis. Sci Rep. 2017; 7(1):1554. PMC: 5431532. DOI: 10.1038/s41598-017-01765-6. View

19.

Kasamatsu A, Uzawa K, Hayashi F, Kita A, Okubo Y, Saito T . Deficiency of lysyl hydroxylase 2 in mice causes systemic endoplasmic reticulum stress leading to early embryonic lethality. Biochem Biophys Res Commun. 2019; 512(3):486-491. DOI: 10.1016/j.bbrc.2019.03.091. View

20.

Cory S, Huang D, Adams J . The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003; 22(53):8590-607. DOI: 10.1038/sj.onc.1207102. View