Transcriptomic analyses of postmortem brains have begun to elucidate 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 postmortem brains of people with ASD. 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 RNA-editing enzymes (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 data sets, including dup15q (genomic duplication of 15q11.2-13.1) cases associated with intellectual disability, highlight RNA-editing dysregulation in ASD and reveal new mechanisms underlying this disorder.
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eCLIP-seq data on FMRP and FXR1P from postmortem human brain have been deposited in GEO with accession code GSE107895. RNA-seq data of Fragile X subjects, carriers and controls have been deposited in GEO with accession codes GSE107867 (NeuroBiobank data set) and GSE117776 (UC Davis FXTAS data set). Fastq files of RNA-seq from the idiopathic ASD, dup15q and control brains were obtained from our previous study9 and are available in the PsychENCODE website (https://www.synapse.org//#!Synapse:syn4921369/wiki/235539). Fastq files of RNA-seq data from the replicate ASD and control cohort are available in GEO (accession GSE51264 / GSE59288).
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Postmortem brain samples used in this study were obtained from the University of Maryland Brain and Tissue Bank, which is a component of the US National Institutes of Health (NIH) NeuroBioBank. We are grateful to the subjects and families who participate in the tissue donation programs. This work was funded by grants from the NIH to X.X. (HG009417 and HG006264), G.W.Y. (HG004659, HG009417, HG007005 and MH107367), S.T. (T32HG002536), E.L.V.N. (HG009530), V.M.C. (MH094681) and R.J.H. (HD 036071). S.T is supported by the UCLA Eureka Scholarship. E.L.V.N. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2172-13). G.A.P. is supported by the National Science Foundation Graduate Research Fellowship. G.R. is supported by NIH fellowship 1F32MH114620.
G.W.Y. is a cofounder of Locana and Eclipse Bioinnovations and member of the scientific advisory boards of Locana, Eclipse Bioinnovations and Aquinnah Pharmaceuticals. E.V.N. is a cofounder and member of the scientific advisory board of Eclipse BioInnovations. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–31
Meta data of brain samples used in this study.
Differential RNA editing sites identified from ASD-control samples in three brain regions.
List of primer sequences used in this study.
Differential editing sites in frontal cortex that correlate with expression of harboring gene.
Module memberships of editing sites from WGCNA.
List of FMPR and FXR1P eCLIP peaks.
Differential RNA editing sites identified in Fragile X samples.
Genes with brain-region-specific differential editing.
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Tran, S.S., Jun, HI., Bahn, J.H. et al. Widespread RNA editing dysregulation in brains from autistic individuals. Nat Neurosci 22, 25–36 (2019). https://doi.org/10.1038/s41593-018-0287-x
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