Widespread RNA editing dysregulation in Autism Spectrum Disorders

Tran, S.; Jun, H.-I.; Bahn, J. H.; Azghadi, A.; Ramaswami, G.; Van Nostrand, E. L.; Nguyen, T. B.; Hsiao, Y.-H. E.; Lee, C.; Pratt, G. A.; Yeo, G. W.; Geschwind, D. H.; Xiao, X.

doi:10.1101/446625

bioRxiv · 10.1101/446625

Widespread RNA editing dysregulation in Autism Spectrum Disorders

Tran, S.·Jun, H.-I.·Bahn, J. H.·Azghadi, A.·Ramaswami, G.·Van Nostrand, E. L.·Nguyen, T. B.·Hsiao, Y.-H. E.·Lee, C.·Pratt, G. A.·Yeo, G. W.·Geschwind, D. H.·Xiao, X.

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Abstract

Autism spectrum disorder (ASD) is a genetically complex, clinically heterogeneous neurodevelopmental disease. Recently, our understanding of the molecular abnormalities in ASD has been expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here, we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of post-mortem ASD brains. Strikingly, we observed a global bias of hypo-editing in ASD brains, common to different brain regions and involving many genes with known neurobiological functions. Through genome-wide protein-RNA binding analyses and detailed molecular assays, 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, thus establishing RNA editing as a molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD and highlight novel mechanisms for RNA editing regulation.

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Tran, S., Jun, H.-I., Bahn, J. H., Azghadi, A., Ramaswami, G., Van Nostrand, E. L., Nguyen, T. B., Hsiao, Y.-H. E., Lee, C., Pratt, G. A., Yeo, G. W., Geschwind, D. H., Xiao, X.. 2018-10-17. Widespread RNA editing dysregulation in Autism Spectrum Disorders. https://doi.org/10.1101/446625

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