Chromatin target of protein arginine methyltransferases alleviates cerebral ischemia/reperfusion-induced injury by regulating RNA alternative splicing
Yu Cui,
Zhaolong Zhang,
Mengfei Lv,
Zhongying Duan,
Wenhao Liu,
Jingchen Gao,
Rui Xu,
Qi Wan
Affiliations
Yu Cui
Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, 308 Ningxia Road, Qingdao, Shandong 266071, China; Qingdao Medical College, Qingdao University, Qingdao 266071, China; Corresponding author
Zhaolong Zhang
Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266000, China
Mengfei Lv
Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, 308 Ningxia Road, Qingdao, Shandong 266071, China; Qingdao Medical College, Qingdao University, Qingdao 266071, China
Zhongying Duan
Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, 308 Ningxia Road, Qingdao, Shandong 266071, China; Qingdao Medical College, Qingdao University, Qingdao 266071, China
Wenhao Liu
Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266000, China
Jingchen Gao
Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, 308 Ningxia Road, Qingdao, Shandong 266071, China
Rui Xu
Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266000, China
Qi Wan
Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, 308 Ningxia Road, Qingdao, Shandong 266071, China; Qingdao Medical College, Qingdao University, Qingdao 266071, China; Corresponding author
Summary: 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.
