Transcriptome-Wide Identification of G-to-A RNA Editing in Chronic Social Defeat Stress Mouse Models

Abstract

Emerging evidence suggests that RNA editing is associated with stress, neurological diseases, and psychiatric disorders. However, the role of G-to-A RNA editing in chronic social defeat stress (CSDS) remains unclear. We herein identified G-to-A RNA editing and its changes in the ventral tegmental area (VTA), a key region of the brain reward system, in CSDS mouse models under emotional stress (ES) and physiological stress (PS) conditions. Our results revealed 3812 high-confidence G-to-A editing events. Among them, 56 events were significantly downregulated while 23 significantly upregulated in CSDS compared to controls. Moreover, divergent editing patterns were observed between CSDS mice under ES and PS conditions, with 42 and 21 events significantly upregulated in PS and ES, respectively. Interestingly, differential RNA editing was enriched in genes with multiple editing events. Genes differentially edited in CSDS included those genetically associated with mental or neurodevelopmental disorders, especially mood disorders, such as FAT atypical cadherin 1 and solute carrier family 6 member 1. Notably, changes of G-to-A RNA editing were also implicated in ionotropic glutamate receptors, a group of well-known targets of adenosine-to-inosine RNA editing. Such results demonstrate dynamic G-to-A RNA editing changes in the brain of CSDS mouse models, underlining its role as a potential molecular mechanism of CSDS and stress-related diseases.

Repeated Winning and Losing Experiences in Chronic Social Conflicts Are Linked to RNA Editing Pattern Difference

“…The sequencing data were then processed as previously described ( 9 ). Sequencing read quality was analyzed using FASTQC.…”

“…Variants were called to identify single nucleotide variations (SNVs) by using VarScan (version 2.4.3) ( 17 ), filtered using a bioinformatic pipeline as described in our previous study ( 9 ), and annotated using the Ensembl Variant Effect Predictor (VEP) ( 18 ). In brief, the SNVs were first filtered as follows: base quality ≥ 25, total sequencing depth ≥ 10, alternative allele depth ≥ 2 and alternative allele frequency (AAF) ≥ 1%.…”

“…Altered adenosine to inosine (A-to-I) editing mediated by adenosine deaminase acting on RNA (ADAR) in 5-hydroxytryptamine receptor 2C ( Htr2c ) ( 7 ) was implicated in the amygdala of BALB/c mice with social isolation-induced aggressive behavior ( 8 ). RNA editing changes have also been found in chronic social defeat stress in mice ( 6 , 9 ). However, by far, the role of A-to-I RNA editing remains to be further elucidated in agonistic interactions and repeated winning and losing experiences.…”

Brain Epitranscriptomic Analysis Revealed Altered A-to-I RNA Editing in Septic Patients

“…The obtained sequencing data were processed as previously described ( Tao et al, 2021 ). In brief, quality control analysis was performed using FASTQC.…”

“…RNA single-nucleotide variation (SNV) was identified using VarScan (version 2.4.3) software ( Koboldt et al, 2012 ) using a standard pipeline described previously ( Tao et al, 2021 ). Annotation of SNVs was performed using the Ensembl Variant Effect Predictor (VEP) ( McLaren et al, 2016 ).…”