Brain Epitranscriptomic Analysis Revealed Altered A-to-I RNA Editing in Septic Patients
Jing-Qian Zhang, Jiaqi Pan, Zhi-Yuan Wei, Chunyan Ren, Fu-Xia Ru, Shou-Yue Xia, Yu-Shan He, Kaisheng Lin, Jian‐Huan Chen
Abstract
Recent studies suggest that RNA editing is associated with impaired brain function and neurological and psychiatric disorders. However, the role of A-to-I RNA editing during sepsis-associated encephalopathy (SAE) remains unclear. In this study, we analyzed adenosine-to-inosine (A-to-I) RNA editing in postmortem brain tissues from septic patients and controls. A total of 3024 high-confidence A-to-I RNA editing sites were identified. In sepsis, there were fewer A-to-I RNA editing genes and editing sites than in controls. Among all A-to-I RNA editing sites, 42 genes showed significantly differential RNA editing, with 23 downregulated and 19 upregulated in sepsis compared to controls. Notably, more than 50% of these genes were highly expressed in the brain and potentially related to neurological diseases. Notably, cis-regulatory analysis showed that the level of RNA editing in six differentially edited genes was significantly correlated with the gene expression, including HAUS augmin-like complex subunit 2 ( HAUS2 ), protein phosphatase 3 catalytic subunit beta ( PPP3CB ), hook microtubule tethering protein 3 ( HOOK3 ), CUB and Sushi multiple domains 1 ( CSMD1 ), methyltransferase-like 7A ( METTL7A ), and kinesin light chain 2 ( KLC2 ). Furthermore, enrichment analysis showed that fewer gene functions and KEGG pathways were enriched by edited genes in sepsis compared to controls. These results revealed alteration of A-to-I RNA editing in the human brain associated with sepsis, thus providing an important basis for understanding its role in neuropathology in SAE.