International Journal of
Reproductive Biomedicine
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Volume 23, Issue 11 (November 2025)
IJRM 2025, 23(11): 897-910 |
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Ethics code: IR.NUMS.REC.1402.002
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Babaei K, Morovat S, Mozdarani H, Naghdipour Mirsadeghi M, Mirhafez S R, Mirzajani E, et al . Integrative RNA‑seq analysis reveals immune‑related hub genes NR4A1 and FOSB in recurrent spontaneous abortion: A bioinformatics study. IJRM 2025; 23 (11) :897-910
URL: http://ijrm.ir/article-1-3457-en.html
URL: http://ijrm.ir/article-1-3457-en.html
Kosar Babaei1 
, Saman Morovat2 , Hossein Mozdarani3 , Misa Naghdipour Mirsadeghi4 , Seyed Reza Mirhafez1 , Ebrahim Mirzajani5 , Mohsen Aziminezhad6 , Ali Akbar Samadani *7
, Saman Morovat2 , Hossein Mozdarani3 , Misa Naghdipour Mirsadeghi4 , Seyed Reza Mirhafez1 , Ebrahim Mirzajani5 , Mohsen Aziminezhad6 , Ali Akbar Samadani *7
1- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
2- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
3- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
4- Department of Gynecology, School of Medicine, Reproductive Health Research Center, Alzahra Hospital, Guilan University of Medical Sciences, Rasht, Iran.
5- Department of Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
6- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran. & Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran. UMR INSERM U 1122, Gene-Environment Interactions in Cardiovascular Pathophysiology (IGE-PCV), University of Lorraine, Nancy, France.
7- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran. ,drsamadani@gums.ac.ir; a.a.hormoz@gmail.com
2- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
3- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
4- Department of Gynecology, School of Medicine, Reproductive Health Research Center, Alzahra Hospital, Guilan University of Medical Sciences, Rasht, Iran.
5- Department of Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
6- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran. & Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran. UMR INSERM U 1122, Gene-Environment Interactions in Cardiovascular Pathophysiology (IGE-PCV), University of Lorraine, Nancy, France.
7- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran. ,
Abstract: (60 Views)
Background: Recurrent spontaneous abortion (RSA) impacts 1-5% of women of reproductive age, constituting a significant health issue. Despite advances in our understanding of RSA, the fundamental molecular mechanisms remain inadequately defined. Examining differentially expressed genes (DEGs) in RSA may yield essential insights into the disease’s pathophysiology and enable the identification of novel ameliorative targets.
Objective: This study aimed to identify key DEGs, elucidate their interaction networks, and uncover potential hub regulators across decidua and villus tissues in RSA vs. control samples.
Materials and Methods: In this bioinformatics study, we analyzed RNA‑seq datasets GSE113790 (decidua) and GSE121950 (villus) from the gene expression omnibus database using illumina‑aligned count matrices. Rigorous batch correction was performed using surrogate variable analysis, followed by differential expression analysis in DESeq2 with thresholds of |log₂FC| ≥ 2 and false discovery rate < 0.05. A high‑confidence protein-protein interaction network was constructed via STRING (confidence > 0.7), and functional enrichment analysis was conducted. Hub genes were identified using the maximal clique centrality, density of maximum neighborhood component, and maximum neighborhood component algorithms in CytoHubba, and the expression of top candidates was visualized across merged datasets.
Results: After correction and integration, 114 protein‑coding DEGs (30 upregulated and 84 downregulated) were identified. The protein-protein interaction network (101 nodes, 116 edges) was significantly enriched over random expectation (p < 1×10⁻¹⁶). Enrichment analysis highlighted immune‑related processes, including neutrophil chemotaxis and cytokine-mediated signaling. Cross‑algorithm analysis revealed NR4A1 and FOSB as consensus hubs, both significantly downregulated in RSA (NR4A1: log₂FC = -2.15, p_adj = 4.78×10⁻²⁰; FOSB: log₂FC = -2.96, p_adj = 2.46×10⁻⁴⁰).
Conclusion: Our integrative approach delineates immune-centric molecular dysfunction in RSA and highlights NR4A1 and FOSB as central regulatory genes that may drive disease pathogenesis. These findings pave the way for experimental validation and functional studies targeting immune-trophoblast signaling to inform diagnostic and therapeutic strategies in RSA.
Objective: This study aimed to identify key DEGs, elucidate their interaction networks, and uncover potential hub regulators across decidua and villus tissues in RSA vs. control samples.
Materials and Methods: In this bioinformatics study, we analyzed RNA‑seq datasets GSE113790 (decidua) and GSE121950 (villus) from the gene expression omnibus database using illumina‑aligned count matrices. Rigorous batch correction was performed using surrogate variable analysis, followed by differential expression analysis in DESeq2 with thresholds of |log₂FC| ≥ 2 and false discovery rate < 0.05. A high‑confidence protein-protein interaction network was constructed via STRING (confidence > 0.7), and functional enrichment analysis was conducted. Hub genes were identified using the maximal clique centrality, density of maximum neighborhood component, and maximum neighborhood component algorithms in CytoHubba, and the expression of top candidates was visualized across merged datasets.
Results: After correction and integration, 114 protein‑coding DEGs (30 upregulated and 84 downregulated) were identified. The protein-protein interaction network (101 nodes, 116 edges) was significantly enriched over random expectation (p < 1×10⁻¹⁶). Enrichment analysis highlighted immune‑related processes, including neutrophil chemotaxis and cytokine-mediated signaling. Cross‑algorithm analysis revealed NR4A1 and FOSB as consensus hubs, both significantly downregulated in RSA (NR4A1: log₂FC = -2.15, p_adj = 4.78×10⁻²⁰; FOSB: log₂FC = -2.96, p_adj = 2.46×10⁻⁴⁰).
Conclusion: Our integrative approach delineates immune-centric molecular dysfunction in RSA and highlights NR4A1 and FOSB as central regulatory genes that may drive disease pathogenesis. These findings pave the way for experimental validation and functional studies targeting immune-trophoblast signaling to inform diagnostic and therapeutic strategies in RSA.
Keywords: Spontaneous abortion, Gene expression profiling, Protein interaction mapping, FOSB, NR4A1.
Type of Study: Original Article |
Subject:
Fertility & Infertility
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