1. Divergent landscapes of A-to-I editing in postmortem and living human brain
- Author
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Miguel Rodriguez de los Santos, Brian H. Kopell, Ariela Buxbaum Grice, Gauri Ganesh, Andy Yang, Pardis Amini, Lora E. Liharska, Eric Vornholt, John F. Fullard, Pengfei Dong, Eric Park, Sarah Zipkowitz, Deepak A. Kaji, Ryan C. Thompson, Donjing Liu, You Jeong Park, Esther Cheng, Kimia Ziafat, Emily Moya, Brian Fennessy, Lillian Wilkins, Hannah Silk, Lisa M. Linares, Brendan Sullivan, Vanessa Cohen, Prashant Kota, Claudia Feng, Jessica S. Johnson, Marysia-Kolbe Rieder, Joseph Scarpa, Girish N. Nadkarni, Minghui Wang, Bin Zhang, Pamela Sklar, Noam D. Beckmann, Eric E. Schadt, Panos Roussos, Alexander W. Charney, and Michael S. Breen
- Subjects
Science - Abstract
Abstract Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.
- Published
- 2024
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