Abstract
Schizophrenia is a complex polygenic disease that is affected by genetic, developmental, and environmental factors. Accumulating evidence indicates that environmental factors such as maternal infection and excessive prenatal neuroinflammation may contribute to the onset of schizophrenia by affecting epigenetic modification. We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding an interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription. Finally, we observed that RP5-998N21.4OE can enhance IFIT2- and IFIT3-mediated immune defense responses through activation of signal transducer and activator of transcription 1 (STAT1) signaling pathway in U251 astrocytoma cells under treatment with the viral mimetic polyinosinic: polycytidylic acid (poly I:C). Taken together, our findings suggest that lncRNA RP5-998N21.4 is a critical regulator of immune defense, providing etiological and therapeutic implications for schizophrenia.
Highlights
Schizophrenia is a complex genetic disease that affects approximately 1% of the global population[1]
RP5-998N21.4 promotes the immune response by activating signal transducer and activator of transcription 1 (STAT1) signaling Since IFIT2 and IFIT3 have been reported to play important roles in the antiviral response through the promotion of Toll-like receptor 3 (TLR3)/IFN-β/STAT1 axis activity[9], we examined whether RP5-998N21.4-mediated upregulation of IFIT2 and IFIT3 activates STAT1 signaling
We observed that polycytidylic acid (poly I):C significantly induced the protein levels of IFIT2, IFIT3, and phosphorylated STAT1 (Fig. 4b and Supplementary Fig. 10), as well as the RNA levels of IFIT2, IFIT3, and CXCL10 (Fig. 4c–e), which were enhanced by RP5-998N21.4 overexpression in U251 cells
Summary
Schizophrenia is a complex genetic disease that affects approximately 1% of the global population[1]. As one of the major epigenetic modifications, long noncoding RNAs (lncRNAs), which are >200 nt in length, play important roles in the regulation of the immune response through different mechanisms, including acting as signals, decoys, guides, or scaffolds[5]. IFIT2 and IFIT3 are IFITs; IFIT3 (ISG60) is involved in poly I:C-induced CXCL10 expression through the Toll-like receptor 3 (TLR3)/IFN-β/STAT1 axis in U373MG human astrocytoma cells[9], suggesting that IFITs may play important roles in a variety of biological processes, including physiological innate immunity and pathological inflammation in the central nervous system. Target genes of RP5-998N21.4, and we identified the seq analysis identified 1722 differentially expressed genes (DEGs, mechanism by which RP5-998N21.4 underlies the development DE-seq: |LogFC| > 0.5, FDR < 0.01) (Supplementary Data 2) induced of schizophrenia by regulating IFIT2- and IFIT3-mediated antiviral immune response pathways. GO–BP analysis revealed significant enrichment of the 1722 DEGs in terms such as “neurogenesis”, “type I
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