Widespread RNA editing dysregulation in brains from autistic individuals

Abstract

Transcriptomic analyses of postmortem brains have begun to elucidate the molecular abnormalities in autism spectrum disorder (ASD). However, a crucial pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here, we profiled global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of post-mortem ASD brains. We observed a global bias for hypoediting in ASD brains, which was shared across brain regions and involved many synaptic genes. We show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR proteins and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations in ASD and Fragile X syndrome, establishing this as a molecular link between these related diseases. Our findings, which are corroborated across multiple datasets, including dup15q cases associated with intellectual disability, highlight RNA editing dysregulation in ASD and reveal novel mechanisms underlying this disorder.

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

“…ADAR2-regulated sites in non-repetitive regions include a number of editing events that alter the protein-coding sequences of neuronal RNAs, including GluR2 , which encodes a glutamate receptor in which RNA editing is necessary for its proper function. Further demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is associated with multiple neurological diseases, including amyotrophic lateral sclerosis, astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al, 2019). Maintaining RNA editing levels is critical for human health, but how RNA editing levels are regulated at specific editing sites across tissues and development is poorly understood.…”

Evolutionary Analyses of RNA Editing and Amino Acid Recoding in Cephalopods

“…It is also apparent that RNA editing comes with a significant cost in the form of random off-target edits by the ADAR enzyme and the general potential for dysregulation. A significant amount of work has highlighted the role of RNA editing in neurodegenerative diseases and aging more generally ( 59,(63)(64)(65)(66)(67). We propose that this "balancing act of RNA editing" ( 64 ) was particularly salient during cephalopod evolution.…”

“…Overall, this hints that modulation of a few core genetic pathways through either RNA editing or gene duplication can affect both brain size and social cognition across vertebrates and invertebrates. Support for this notion comes from recent work demonstrating dysregulation of RNA editing in autistic brains ( 59 ). Additionally, the autism-risk genes shown to modulate sociality in bees are enriched for RNA editing functions ( 51 ).…”

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

“…Consequently, these reads may be left unmapped and hinder accurate detection of editing in these regions. To rescue reads that were originally unmapped due to high density of editing activity, we applied a hyperediting pipeline and combined the recovered reads with uniquely mapped reads for downstream analyses 32,84 . To analyze editing sites of high confidence, we downloaded the REDIportal database, comprising over 4 million editing sites identified across 55 tissues of 150 healthy humans from GTEx (http://srv00.recas.ba.infn.it/atlas/) 33 .…”

“…Similarly, we calculated the AUC of the distribution of closest distances between eCLIP peaks and controls, for each of 10,000 sets of random controls. We computed the p-value of the AUC for differential editing sites from the normal distribution fit to the AUC values of control sets 32 Editing Rank Expression Rank mitochondrial electron transport, NADH to ubiquinone nucleobase−containing compound metabolic process cellular metabolic process glycosaminoglycan metabolic process glycosphingolipid metabolic process cellular protein metabolic process one−carbon metabolic process sphingolipid metabolic process fatty acid biosynthetic process water−soluble vitamin metabolic process vitamin metabolic process xenobiotic metabolic process mRNA metabolic process RNA metabolic process positive regulation of catalytic activity retrograde vesicle−mediated transport, Golgi to ER SRP−dependent cotranslational protein targeting to membrane peptidyl−serine phosphorylation proteolysis protein glycosylation protein autoubiquitination protein stabilization positive regulation of translation translational termination translational elongation translational initiation translation tRNA processing nuclear−transcribed mRNA catabolic process, nonsense−mediated decay regulation of transcription, DNA−templated transcription, DNA−templated DNA replication CENP−A containing nucleosome assembly nucleosome assembly stem cell population maintenance response to UV cellular response to hypoxia mitotic cell cycle antigen processing and presentation of exogenous peptide antigen via MHC class II positive regulation of I−kappaB kinase/NF−kappaB signaling negative regulation of type I interferon production innate immune response viral transcription viral life cycle viral process positive regulation of defense response to virus by host negative regulation of viral genome replication defense response to virus defense response to bacterium defense response For an individual cancer type, genes were ranked by the signed significance of RNA editing differences (M-E). Genes with higher editing in the M phenotype are at lower ranks, while those with higher editing levels in E tumors are at higher ranks.…”