Mechanistic Insight Into the Regulation of Immune-Related Genes Expression in Autism Spectrum Disorder

Hani Sabaie; Hossein Dehghani; Shadi Shiva; Mohammad Reza Asadi; Omidvar Rezaei; Mohammad Taheri; Maryam Rezazadeh

doi:10.3389/fmolb.2021.754296

Mechanistic Insight Into the Regulation of Immune-Related Genes Expression in Autism Spectrum Disorder

Front Mol Biosci. 2021 Oct 21:8:754296. doi: 10.3389/fmolb.2021.754296. eCollection 2021.

Authors

Hani Sabaie^{1

2}, Hossein Dehghani³, Shadi Shiva⁴, Mohammad Reza Asadi^{1

2}, Omidvar Rezaei⁵, Mohammad Taheri^{5

6}, Maryam Rezazadeh^{1

2}

Affiliations

¹ Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
² Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
³ Department of Molecular Medicine, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
⁴ Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
⁵ Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁶ Institute of Human Genetics, Jena University Hospital, Jena, Germany.

Abstract

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder featuring impairment in verbal and non-verbal interactions, defects in social interactions, stereotypic behaviors as well as restricted interests. In recent times, the incidence of ASD is growing at a rapid pace. In spite of great endeavors devoted to explaining ASD pathophysiology, its precise etiology remains unresolved. ASD pathogenesis is related to different phenomena associated with the immune system; however, the mechanisms behind these immune phenomena as well as the potential contributing genes remain unclear. In the current work, we used a bioinformatics approach to describe the role of long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) in the peripheral blood (PB) samples to figure out the molecular regulatory procedures involved in ASD better. The Gene Expression Omnibus database was used to obtain the PB microarray dataset (GSE89594) from the subjects suffering from ASD and control subjects, containing the data related to both mRNAs and lncRNAs. The list of immune-related genes was obtained from the ImmPort database. In order to determine the immune-related differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs), the limma package of R software was used. A protein-protein interaction network was developed for the immune-related DEmRNAs. By employing the Human MicroRNA Disease Database, DIANA-LncBase, and DIANA-TarBase databases, the RNA interaction pairs were determined. We used the Pearson correlation coefficient to discover the positive correlations between DElncRNAs and DEmRNAs within the ceRNA network. Finally, the lncRNA-associated ceRNA network was created based on DElncRNA-miRNA-DEmRNA interactions and co-expression interactions. In addition, the KEGG enrichment analysis was conducted for immune-related DEmRNAs found within the constructed network. This work found four potential DElncRNA-miRNA-DEmRNA axes in ASD pathogenesis, including, LINC00472/hsa-miR-221-3p/PTPN11, ANP32A-IT1/hsa-miR-182-5p/S100A2, LINC00472/hsa-miR-132-3p/S100A2, and RBM26-AS1/hsa-miR-182-5p/S100A2. According to pathway enrichment analysis, the immune-related DEmRNAs were enriched in the "JAK-STAT signaling pathway" and "Adipocytokine signaling pathway." An understanding of regulatory mechanisms of ASD-related immune genes would provide novel insights into the molecular mechanisms behind ASD pathogenesis.

Keywords: autism spectrum disorder; bioinformatics analysis; competing endogenous RNA; immune response; long non-coding RNA.