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.

Keywords: RNA editing; depression; emotional stress; physical stress; post-traumatic stress disorder; social defeat; ventral tegmental area.

FIGURE 1

G-to-A RNA editing events identified from adult mouse VTA transcriptome. The red dots denotes the events observed across all chromosomes in the mouse genome (A). The blue dots show mean expression levels of genes. And the lines denote interaction between the G-to-A RNA editing events, with the blue-to-red gradient indicated the correlation co-efficient r. The interaction among the top 100 frequently observed editing events is shown. (B) The G-to-A RNA editing events result in various types of mRNA variants. (C) About half of these missense events are predicted by SIFT to possibly be deleterious on the encoded proteins.

FIGURE 2

Comparison of genomic locations of G-to-A RNA editing events in controls and CSDS.

FIGURE 3

Differential G-to-A RNA editing events between CSDS and controls. (A) A total of 79 events are differentially edited between CSDS and controls, including 56 and 23 are upregulated and downregulated, respectively. (B) Principle component analysis of the 79 events differentially edited between CSDS and controls.

FIGURE 4

The events that are the most significantly associated with CSDS. The top three upregulated events (A), and top three downregulated events (B) in CSDS compared to controls are shown.

FIGURE 5

Gene ontology and KEGG pathways erniched in gene with CSDS-associated G-to-A RNA editing. The items with the most significant P-values are shown for (A) biological processes, (B) molecular functions, and (C) cellular components, as well as (D) KEGG pathways enriched in either CSDS or controls. CSDS, chronic social defeat stress.

FIGURE 6

Comparison of genomic locations of G-to-A RNA editing events between ES and PS.

FIGURE 7

Differential G-to-A RNA editing events between PS and ES. (A) 63 events showed differential editing levels between CSDS and controls, including 42 and 21 are upregulated in PS and ES, respectively. (B) Principle component analysis of these Differential G-to-A RNA editing between PS and ES.

FIGURE 8

The top G-to-A RNA editing with significant difference between PS and ES. The top three upregulated events in ES (A), and top three downregulated events (B) in PS are shown.

FIGURE 9

Gene ontology and KEGG pathways associated with divergent G-to-A RNA editing patterns between PS and ES. The items with the most significant P-values are shown for (A) biological processes, (B) molecular functions, and (C) cellular components, as well as (D) KEGG pathways. ES, emotional stress; PS: physical stress.