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. 2021 Nov;13(22):1797-1815.
doi: 10.2217/epi-2021-0296. Epub 2021 Nov 2.

Construction of a lncRNA-miRNA-mRNA network to determine the key regulators of the Th1/Th2 imbalance in multiple sclerosis

Hanieh Azari  1 , Elham Karimi  1 , Mohammad Shekari  1   2 , Ahmad Tahmasebi  3 , Amin Reza Nikpoor  2 , Ahmad Agha Negahi  4 , Nima Sanadgol  5 , Pegah Mousavi  1   2
Affiliations

Construction of a lncRNA-miRNA-mRNA network to determine the key regulators of the Th1/Th2 imbalance in multiple sclerosis

Hanieh Azari et al. Epigenomics. 2021 Nov.

Abstract

Aim: The exact epigenetic mechanisms that determine the balance of T helper (Th)1 and Th2 cells and autoimmune responses in multiple sclerosis (MS) remain unclear. We aim to clarify these. Methods: A combination of bioinformatics analysis and molecular evaluations was utilized to identify master hub genes. Results: A competitive endogenous RNA network containing six long noncoding RNAs (lncRNAs), 21 miRNAs and 86 mRNAs was provided through enrichment analysis and a protein-protein interaction network. NEAT1 and MALAT1 were found as differentially expressed lncRNAs using Gene Expression Omnibus (GSE21942). Quantitative real-time PCR results demonstrate dysregulation in the RUNX3 (a regulator of Th1/Th2 balance), GATA3 and TBX21, as well as miR-544a and miR-210-3p (which directly target RUNX3). ELISA also confirmed an imbalance in IFN-γ (Th1)/IL-4 (Th2) in MS patients. Conclusion: Our findings introduce novel biomarkers leading to Th1/Th2 imbalance in MS.

Keywords: RUNX3; Th1/Th2 imbalance; ceRNA network; miR-210-3p; miR-544a; multiple sclerosis; real-time PCR.

Plain language summary

Lay abstract Studies have shown that irregular control of noncoding RNAs (ncRNAs) in immune responses can lead to multiple sclerosis. T helper (Th)1 and Th2 cells balance plays an important role in regulating inflammation in this disease. In this study, to investigate the molecular factors that may disrupt this balance, we investigated the role of ncRNAs. Our results suggest that miR-210-3p and miR-544a irregularities can disrupt the Th1/Th2 balances through targeting the RUNX3 gene, which consequently leads to IFNγ/IL4 imbalance. It is also clarified that NEAT1 and MALAT1 long noncoding RNAs also have a role in this imbalance exerting their effect through miR-210-3p and miR-544a. This molecular pathway may provide significant information on multiple sclerosis disease development.

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