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Widespread RNA editing dysregulation in Autism Spectrum Disorders

Stephen Tran, Hyun-Ik Jun, Jae Hoon Bahn, Adel Azghadi, Gokul Ramaswami, Eric L. Van Nostrand, Thai B. Nguyen, Yun-Hua E. Hsiao, Changhoon Lee, Gabriel A. Pratt, Gene W. Yeo, Daniel H. Geschwind, Xinshu Xiao
doi: https://doi.org/10.1101/446625
Stephen Tran
1Bioinformatics Interdepartmental Program, UCLA, Los Angeles, California, CA, 90095, USA
2Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, CA, 90095, USA
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Hyun-Ik Jun
2Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, CA, 90095, USA
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Jae Hoon Bahn
2Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, CA, 90095, USA
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Adel Azghadi
2Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, CA, 90095, USA
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Gokul Ramaswami
3Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, CA, 90095, USA
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Eric L. Van Nostrand
4Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
5Stem Cell Program, UCSD, La Jolla, CA, 92093, USA
6Institute for Genomic Medicine, UCSD, La Jolla, CA, 92093, USA
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Thai B. Nguyen
4Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
5Stem Cell Program, UCSD, La Jolla, CA, 92093, USA
6Institute for Genomic Medicine, UCSD, La Jolla, CA, 92093, USA
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Yun-Hua E. Hsiao
7Department of Bioengineering, UCLA, Los Angeles, California, CA, 90095, USA
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Changhoon Lee
3Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, CA, 90095, USA
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Gabriel A. Pratt
4Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
5Stem Cell Program, UCSD, La Jolla, CA, 92093, USA
6Institute for Genomic Medicine, UCSD, La Jolla, CA, 92093, USA
8Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, 92093, USA
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Gene W. Yeo
4Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
5Stem Cell Program, UCSD, La Jolla, CA, 92093, USA
6Institute for Genomic Medicine, UCSD, La Jolla, CA, 92093, USA
8Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, 92093, USA
9Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117593, Singapore
10Molecular Engineering Laboratory, A*STAR, 138673, Singapore
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Daniel H. Geschwind
3Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, CA, 90095, USA
11Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, UCLA, CA, 90095, USA.
12Department of Human Genetics, David Geffen School of Medicine, UCLA, California 90095, USA.
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  • For correspondence: dhg@mednet.ucla.edu gxxiao@ucla.edu
Xinshu Xiao
1Bioinformatics Interdepartmental Program, UCLA, Los Angeles, California, CA, 90095, USA
2Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, CA, 90095, USA
7Department of Bioengineering, UCLA, Los Angeles, California, CA, 90095, USA
12Department of Human Genetics, David Geffen School of Medicine, UCLA, California 90095, USA.
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  • For correspondence: dhg@mednet.ucla.edu gxxiao@ucla.edu
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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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Posted October 17, 2018.
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Widespread RNA editing dysregulation in Autism Spectrum Disorders
Stephen Tran, Hyun-Ik Jun, Jae Hoon Bahn, Adel Azghadi, Gokul Ramaswami, Eric L. Van Nostrand, Thai B. Nguyen, Yun-Hua E. Hsiao, Changhoon Lee, Gabriel A. Pratt, Gene W. Yeo, Daniel H. Geschwind, Xinshu Xiao
bioRxiv 446625; doi: https://doi.org/10.1101/446625
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Widespread RNA editing dysregulation in Autism Spectrum Disorders
Stephen Tran, Hyun-Ik Jun, Jae Hoon Bahn, Adel Azghadi, Gokul Ramaswami, Eric L. Van Nostrand, Thai B. Nguyen, Yun-Hua E. Hsiao, Changhoon Lee, Gabriel A. Pratt, Gene W. Yeo, Daniel H. Geschwind, Xinshu Xiao
bioRxiv 446625; doi: https://doi.org/10.1101/446625

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