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Abstract
MicroRNAs are powerful regulators of gene expression in physiological and pathological conditions. We previously showed that the dysregulation of miR-384 resulted in a T helper cell 17 (Th17) imbalance and contributed to the pathogenesis of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. In this study, we evaluated the molecular mechanisms underlying the abnormal increase in miR-384. We did not detect typical CpG islands in the Mir384 promoter. Based on a bioinformatics analysis of the promoter, we identified three conserved transcription factor binding regions (RI, RII, and RIII), two of which (RII and RIII) were cis-regulatory elements. Furthermore, we showed that signal transducer and activator of transcription 3 (STAT3) bound to specific sites in RII and RIII based on chromatin immunoprecipitation, electrophoretic mobility shift assays, and site-specific mutagenesis. During Th17 polarization in vitro, STAT3 activation up-regulated miR-384, while a STAT3 phosphorylation inhibitor decreased miR-384 levels and reduced the percentage of IL-17+ cells, IL-17 secretion, and expression of the Th17 lineage marker Rorγt. Moreover, the simultaneous inhibition of STAT3 and miR-384 could further block Th17 polarization. These results indicate that STAT3, rather than DNA methylation, contributes to the regulation of miR-384 during Th17 polarization.
Highlights
MicroRNAs are a class of important small non-coding RNAs that either inhibit the translation of or trigger the degradation of target mRNAs by binding to 3 -untranslated regions (Saliminejad et al, 2019)
We have previously shown that miR-384 levels are abnormally increased in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) (Qu et al, 2017), a central nervous system autoimmune disease caused by inappropriate inflammation and the infiltration of IL-17-producing CD4+ T helper (Th17) cells (Zhu et al, 2017; Zhang et al, 2019)
We evaluated the upstream molecular mechanisms underlying the regulation of miR-384 and found that miR-384 could be activated by p-signal transducer and activator of transcription 3 (STAT3), explaining the abnormal increase in this miRNA during T helper cell 17 (Th17) polarization
Summary
MicroRNAs (miRNAs) are a class of important small non-coding RNAs that either inhibit the translation of or trigger the degradation of target mRNAs by binding to 3 -untranslated regions (Saliminejad et al, 2019). About 1000 human miRNAs have been identified They are thought to regulate more than 50% of protein-coding genes in the genome and thereby contribute to a wide array of complex cellular processes, including cell proliferation, differentiation, invasion, metastasis, apoptosis, and cell–cell communication (Selbach et al, 2008; Bayraktar et al, 2017). MiRNAs are involved in many diseases, such as cancer, cardiovascular diseases, metabolic diseases, neurodegenerative diseases, and autoimmune diseases (Paul et al, 2018). They are used as diagnostic, prognostic, and predictive biomarkers (Jamali et al, 2018; Petrovic and Ergun, 2018; Salehi and Sharifi, 2018), and miRNA-based therapies have shown promising results. The factors contributing to the disruption of specific miRNAs in certain diseases are unclear
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