Comparative RNA editing in autistic and neurotypical cerebella

Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally-regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000×) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme ADARB1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella, and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism.

Identification of human RNA editing sites: A historical perspective

“…RNA editing is quite prevalent throughout the transcriptome, with almost all adenosine nucleotides edited to some degree within Alu repeats [53]. Analyses using RNA-seq datasets have already started to shed light on previously uncharacterized topics such as the evolutionary conservation of editing in primates [54], the tissue-specificity of particular editing sites [55], and the role of RNA editing in diseases such as cancer [56–58] and neurological disorders [59, 60]. Still there are many critical unanswered questions.…”

An Update on the Epigenetics of Psychotic Diseases and Autism

“…Altered editing of HTR2C, GRIK2, GRIA4 and more than twofold increase in overall editing variance of other synaptic genes was observed in postmortem brains of patients with autism [135]. Interestingly, early life stress such as infant maternal separation in mice increased HTR2C mRNA editing which was retained to the adulthood and could be reversed by chronic fluoxetine treatment during adolescence [136].…”

A-to-I editing of coding and non-coding RNAs by ADARs

“…The 5-HT 2C R mRNA-editing mutant mice (both over- and under-edited) exhibit anti-depressive and exaggerated anxiety- like behaviours, indicating a relevance of 5-HT 2C R mRNA editing to psychiatric disorders 89 . An association of altered editing patterns of 5-HT 2C R with several psychiatric disorders, including anxiety, depression, bipolar disorder, schizophrenia and suicide, as well as with autism, has been reported, although the findings have often been inconsistent owing to the difficulty of analysing post-mortem human brain samples 28,29,90 .…”