Cellular and genetic drivers of RNA editing variation in the human brain

Winston H. Cuddleston, Junhao Li, Xuanjia Fan, Alexey Kozenkov, Matthew Lalli, Shahrukh Khalique, Stella Dracheva, Eran A. Mukamel and Michael S. Breen ()
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Winston H. Cuddleston: Department of Psychiatry at Mount Sinai
Junhao Li: University of California, San Diego
Xuanjia Fan: Department of Psychiatry at Mount Sinai
Alexey Kozenkov: Department of Psychiatry at Mount Sinai
Matthew Lalli: Department of Psychiatry at Mount Sinai
Shahrukh Khalique: Department of Psychiatry at Mount Sinai
Stella Dracheva: Department of Psychiatry at Mount Sinai
Eran A. Mukamel: University of California, San Diego
Michael S. Breen: Department of Psychiatry at Mount Sinai

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Posttranscriptional adenosine-to-inosine modifications amplify the functionality of RNA molecules in the brain, yet the cellular and genetic regulation of RNA editing is poorly described. We quantify base-specific RNA editing across three major cell populations from the human prefrontal cortex: glutamatergic neurons, medial ganglionic eminence-derived GABAergic neurons, and oligodendrocytes. We identify more selective editing and hyper-editing in neurons relative to oligodendrocytes. RNA editing patterns are highly cell type-specific, with 189,229 cell type-associated sites. The cellular specificity for thousands of sites is confirmed by single nucleus RNA-sequencing. Importantly, cell type-associated sites are enriched in GTEx RNA-sequencing data, edited ~twentyfold higher than all other sites, and variation in RNA editing is largely explained by neuronal proportions in bulk brain tissue. Finally, we uncover 661,791 cis-editing quantitative trait loci across thirteen brain regions, including hundreds with cell type-associated features. These data reveal an expansive repertoire of highly regulated RNA editing sites across human brain cell types and provide a resolved atlas linking cell types to editing variation and genetic regulatory effects.

Date: 2022
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DOI: 10.1038/s41467-022-30531-0

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