Chromatin target of protein arginine methyltransferases alleviates cerebral ischemia/reperfusion-induced injury by regulating RNA alternative splicing

Abstract

RNA splicing is a post-transcriptional event that regulates many physiological and pathological events. However, whether RNA splicing regulates cerebral I/R-induced brain injury remains largely unknown. In this study, we found that the chromatin target of Prmts (CHTOP) was highly expressed in neurons, and anti-inflammatory cytokine interleukin-10 (IL-10) upregulates its expression after ischemia. In addition, overexpression or knockdown of CHTOP alleviated or exacerbated neuronal death in both experimental stroke mice and cultured neurons. Mechanistically, RNA alternative splicing is altered early after oxygen and glucose deprivation/reoxygenation (OGD/R). CHTOP interacted with nuclear speckle-related proteins to regulate alternative mRNA splicing of neuronal survival-related genes after OGD/R. In addition, I/R injury-induced cytokines IL-10 regulate CHTOP-mediated RNA splicing to alleviate ischemic brain injury. Taken together, this study reveals the alteration of RNA splicing after OGD/R and identifies the IL-10-CHTOP-RNA splicing axis as a modulator of brain injury, which may be promising therapeutic targets for ischemic stroke.