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Widespread RNA editing dysregulation in brains from autistic individuals

Abstract

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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Fig. 1: Transcriptome-wide differential editing in the frontal cortex of subjects with ASD.
Fig. 2: Global analysis reveals potential regulators of differential editing in the frontal cortex of ASD.
Fig. 3: FMRP and FXR1P regulate RNA editing.
Fig. 4: Transcriptome-wide differential editing in the frontal cortex of Fragile X subjects and controls.
Fig. 5: RNA editing dysregulation in different brain regions.
Fig. 6: Hypoediting in three brain regions of dup15q subjects.

Data availability

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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Acknowledgements

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.

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Affiliations

Authors

Contributions

S.S.T. carried out data analyses with input from G.R. H.I.J., J.H.B. and A.A. performed molecular biology experiments. E.L.V.N., T.B.N., G.A.P. and G.W.Y carried out eCLIP experiments and data processing. Y.H.E.H. contributed to data visualization. C.L. carried out ASD RNA-seq data generation. V.M.C. and R.J.H. provided postmortem Fragile X and control samples. S.S.T, D.H.G. and X.X. designed the study, interpreted the results and wrote the manuscript.

Corresponding authors

Correspondence to Daniel H. Geschwind or Xinshu Xiao.

Ethics declarations

Competing interests

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.

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Supplementary information

Supplementary Figures 1–31

Supplementary Figures 1–31

Reporting Summary

Supplementary Table 1

Meta data of brain samples used in this study.

Supplementary Table 2

Differential RNA editing sites identified from ASD-control samples in three brain regions.

Supplementary Table 3

List of primer sequences used in this study.

Supplementary Table 4

Differential editing sites in frontal cortex that correlate with expression of harboring gene.

Supplementary Table 5

Module memberships of editing sites from WGCNA.

Supplementary Table 6

List of FMPR and FXR1P eCLIP peaks.

Supplementary Table 7

Differential RNA editing sites identified in Fragile X samples.

Supplementary Table 8

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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