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Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing

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ABSTRACT

A-to-I RNA editing is an important process for generating molecular diversity in the brain through modification of transcripts encoding several proteins important for neuronal signaling. We investigated the relationships between the extent of editing at multiple substrate transcripts (5HT2C, MGLUR4, CADPS, GLUR2, GLUR4, and GABRA3) in brain tissue obtained from adult humans and rhesus macaques. Several patterns emerged from these studies revealing conservation of editing across primate species. Additionally, variability in the human population allows us to make novel inferences about the co-regulation of editing at different editing sites and even across different brain regions.

Electronic supplementary material: The online version of this article (doi:10.1186/s13041-017-0291-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


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ADAR1 and ADAR2 expression in human and rhesus macaque brain tissue. a The mean ADAR1:ADAR2 ratio in each brain region is plotted (human results indicated by shaded bars) and no significant differences were observed between species. Asterisks represent significant differences between mean combined ratios of both species in each brain region as determined by T-test (*p < .01, **p < .001). b Linear regression analysis of ADAR1 and ADAR2 expression in rhesus macaque reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .93) c Linear regression analysis of ADAR1 and ADAR2 expression in human reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .91) and striatum (p < .0001, r2 = .72)
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Fig5: ADAR1 and ADAR2 expression in human and rhesus macaque brain tissue. a The mean ADAR1:ADAR2 ratio in each brain region is plotted (human results indicated by shaded bars) and no significant differences were observed between species. Asterisks represent significant differences between mean combined ratios of both species in each brain region as determined by T-test (*p < .01, **p < .001). b Linear regression analysis of ADAR1 and ADAR2 expression in rhesus macaque reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .93) c Linear regression analysis of ADAR1 and ADAR2 expression in human reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .91) and striatum (p < .0001, r2 = .72)

Mentions: We investigated the relationship between ADAR mRNA expression and A-to-I editing by comparing overall mRNA expression levels with the editing profiles determined for each sample. In primates, ADAR1 and ADAR2 are located on Chromosome 1 and Chromosome 21 respectively and the pre-mRNAs encoded by each undergo alternative splicing generating several unique transcripts [16–18]. The Taqman Probe (Life, CA) assays used for these studies detect all major ADAR1 and ADAR2 variants respectively. The probes were designed to detect all splice variants of each respective ADAR so the data presented represents a sum total of ADAR mRNA expression. ADAR1 mRNA was found to be 20–60 fold more abundant than ADAR2 in each tissue analyzed. Interestingly, we found that each respective tissue had a characteristic ratio of ADAR1:ADAR2 mRNA and that this ratio was maintained over large expression range (Fig. 5; Cortex ADAR1:ADAR2 18.64+/−2.09, Striatum ADAR1:ADAR2 52.46 +/−4.7). These brain region specific characteristic mRNA ratios were similar in both primate species (Fig. 3; t-test Human vs Monkey mRNA ratio p > .05 in each brain region). However, neither the ADAR mRNA expression levels nor the ADAR1:ADAR2 ratios correlate with the extent of editing at any of the substrates analyzed in this study (Additional file 2: Figure S2 and Additional file 3: Figure S3) (). The consistent ratio of ADAR1:ADAR2 across this large range supports the hypothesis that transcription of these two genes may be co-regulated and suggests that the ratio of ADAR1:ADAR2 is more important for normal physiology than the absolute level of expression.Fig. 5


Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing
ADAR1 and ADAR2 expression in human and rhesus macaque brain tissue. a The mean ADAR1:ADAR2 ratio in each brain region is plotted (human results indicated by shaded bars) and no significant differences were observed between species. Asterisks represent significant differences between mean combined ratios of both species in each brain region as determined by T-test (*p < .01, **p < .001). b Linear regression analysis of ADAR1 and ADAR2 expression in rhesus macaque reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .93) c Linear regression analysis of ADAR1 and ADAR2 expression in human reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .91) and striatum (p < .0001, r2 = .72)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5382662&req=5

Fig5: ADAR1 and ADAR2 expression in human and rhesus macaque brain tissue. a The mean ADAR1:ADAR2 ratio in each brain region is plotted (human results indicated by shaded bars) and no significant differences were observed between species. Asterisks represent significant differences between mean combined ratios of both species in each brain region as determined by T-test (*p < .01, **p < .001). b Linear regression analysis of ADAR1 and ADAR2 expression in rhesus macaque reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .93) c Linear regression analysis of ADAR1 and ADAR2 expression in human reveals a significant correlation between ADAR expression in cortex (p < .0001, r2 = .91) and striatum (p < .0001, r2 = .72)
Mentions: We investigated the relationship between ADAR mRNA expression and A-to-I editing by comparing overall mRNA expression levels with the editing profiles determined for each sample. In primates, ADAR1 and ADAR2 are located on Chromosome 1 and Chromosome 21 respectively and the pre-mRNAs encoded by each undergo alternative splicing generating several unique transcripts [16–18]. The Taqman Probe (Life, CA) assays used for these studies detect all major ADAR1 and ADAR2 variants respectively. The probes were designed to detect all splice variants of each respective ADAR so the data presented represents a sum total of ADAR mRNA expression. ADAR1 mRNA was found to be 20–60 fold more abundant than ADAR2 in each tissue analyzed. Interestingly, we found that each respective tissue had a characteristic ratio of ADAR1:ADAR2 mRNA and that this ratio was maintained over large expression range (Fig. 5; Cortex ADAR1:ADAR2 18.64+/−2.09, Striatum ADAR1:ADAR2 52.46 +/−4.7). These brain region specific characteristic mRNA ratios were similar in both primate species (Fig. 3; t-test Human vs Monkey mRNA ratio p > .05 in each brain region). However, neither the ADAR mRNA expression levels nor the ADAR1:ADAR2 ratios correlate with the extent of editing at any of the substrates analyzed in this study (Additional file 2: Figure S2 and Additional file 3: Figure S3) (). The consistent ratio of ADAR1:ADAR2 across this large range supports the hypothesis that transcription of these two genes may be co-regulated and suggests that the ratio of ADAR1:ADAR2 is more important for normal physiology than the absolute level of expression.Fig. 5

View Article: PubMed Central - PubMed

ABSTRACT

A-to-I RNA editing is an important process for generating molecular diversity in the brain through modification of transcripts encoding several proteins important for neuronal signaling. We investigated the relationships between the extent of editing at multiple substrate transcripts (5HT2C, MGLUR4, CADPS, GLUR2, GLUR4, and GABRA3) in brain tissue obtained from adult humans and rhesus macaques. Several patterns emerged from these studies revealing conservation of editing across primate species. Additionally, variability in the human population allows us to make novel inferences about the co-regulation of editing at different editing sites and even across different brain regions.

Electronic supplementary material: The online version of this article (doi:10.1186/s13041-017-0291-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus