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Widespread RNA editing dysregulation in Autism Spectrum Disorders [eCLIP-seq]

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly 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 ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107895 | GEO | 2018/12/14

REPOSITORIES: GEO

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Widespread RNA editing dysregulation in Autism Spectrum Disorders [RNA-Seq]

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly 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 ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.

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Convergent coexpression of autism associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies

Project description:Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult and genetic studies depending on presence of deleterious variation may be limited in implicating highly intolerant genes with shorter coding sequences. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N = 993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) in human neurons (N = 17). Across 71 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. Tissue specific convergence of risk genes is a generalizable phenomenon, shown additionally in schizophrenia (brain) and atrial fibrillation (heart). The degree of this convergence in ASD is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.32, P = 3.03 ×10−65) as well as differential expression in post-mortem ASD brains (rho = -0.23, P = 2.39×10−43). After removing all genes statistically associated with ASD, the remaining positively convergent genes showed intolerance to functional mutations, had shorter coding lengths than the ASD genes and were enriched for genes with clinical reports of potential pathogenic contribution to ASD. These results indicate that leveraging convergent coexpression can identify potentially novel risk genes that are unlikely to be discovered by sequencing studies. Overall, this work provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known risk genes of multiple diseases, and proposes novel ASD risk gene candidates.

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