Divergent landscapes of A-to-I editing in postmortem and living human brain

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 ()
Additional contact information
Miguel Rodriguez de los Santos: Icahn School of Medicine at Mount Sinai
Brian H. Kopell: Icahn School of Medicine at Mount Sinai
Ariela Buxbaum Grice: Icahn School of Medicine at Mount Sinai
Gauri Ganesh: Icahn School of Medicine at Mount Sinai
Andy Yang: Icahn School of Medicine at Mount Sinai
Pardis Amini: Icahn School of Medicine at Mount Sinai
Lora E. Liharska: Icahn School of Medicine at Mount Sinai
Eric Vornholt: Icahn School of Medicine at Mount Sinai
John F. Fullard: Icahn School of Medicine at Mount Sinai
Pengfei Dong: Icahn School of Medicine at Mount Sinai
Eric Park: Icahn School of Medicine at Mount Sinai
Sarah Zipkowitz: Icahn School of Medicine at Mount Sinai
Deepak A. Kaji: Icahn School of Medicine at Mount Sinai
Ryan C. Thompson: Icahn School of Medicine at Mount Sinai
Donjing Liu: Icahn School of Medicine at Mount Sinai
You Jeong Park: Icahn School of Medicine at Mount Sinai
Esther Cheng: Icahn School of Medicine at Mount Sinai
Kimia Ziafat: Icahn School of Medicine at Mount Sinai
Emily Moya: Icahn School of Medicine at Mount Sinai
Brian Fennessy: Icahn School of Medicine at Mount Sinai
Lillian Wilkins: Icahn School of Medicine at Mount Sinai
Hannah Silk: Icahn School of Medicine at Mount Sinai
Lisa M. Linares: Icahn School of Medicine at Mount Sinai
Brendan Sullivan: Icahn School of Medicine at Mount Sinai
Vanessa Cohen: Icahn School of Medicine at Mount Sinai
Prashant Kota: Icahn School of Medicine at Mount Sinai
Claudia Feng: Icahn School of Medicine at Mount Sinai
Jessica S. Johnson: Icahn School of Medicine at Mount Sinai
Marysia-Kolbe Rieder: Icahn School of Medicine at Mount Sinai
Joseph Scarpa: Icahn School of Medicine at Mount Sinai
Girish N. Nadkarni: Icahn School of Medicine at Mount Sinai
Minghui Wang: Icahn School of Medicine at Mount Sinai
Bin Zhang: Icahn School of Medicine at Mount Sinai
Pamela Sklar: Icahn School of Medicine at Mount Sinai
Noam D. Beckmann: Icahn School of Medicine at Mount Sinai
Eric E. Schadt: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai
Alexander W. Charney: Icahn School of Medicine at Mount Sinai
Michael S. Breen: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-15

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.

Date: 2024
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DOI: 10.1038/s41467-024-49268-z

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