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.

Details

Title
LncRNA RP5-998N21.4 promotes immune defense through upregulation of IFIT2 and IFIT3 in schizophrenia
Author
Guo, Bo 1 ; Jiang, Tingyun 2 ; Wu, Fengchun 3 ; Ni, Hongyu 4 ; Ye, Junping 4 ; Wu, Xiaohui 4 ; Ni, Chaoying 4 ; Jiang, Meijun 5 ; Ye, Linyan 4 ; Li, Zhongwei 4 ; Zheng, Xianzhen 5 ; Li, Shufen 4 ; Yang, Qiong 3 ; Wang, Zhongju 4 ; Huang, Xingbing 3   VIAFID ORCID Logo  ; Zhao, Cunyou 6   VIAFID ORCID Logo 

1  Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471); Southern Medical University, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471) 
2  The Third People’s Hospital of Zhongshan, Zhongshan, China (GRID:grid.284723.8) 
3  the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Department of Psychiatry, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072) 
4  Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471) 
5  Guangdong Academy of Medical Sciences, Guangdong Mental Health Center, Guangdong Provincial People’s Hospital, Guangzhou, China (GRID:grid.410643.4) 
6  Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471); Southern Medical University, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471); Southern Medical University, Experimental Education/Administration Center, School of Basic Medical Science, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471); Department of Rehabilitation, Zhujiang Hospital of Southern Medical University, Guangzhou, China (GRID:grid.417404.2) (ISNI:0000 0004 1771 3058) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
2334265X
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41537-021-00195-8
ProQuest document ID
2634667558
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.