Mudra Choudhury, Ting Fu, Kofi Amoah, Hyun-Ik Jun, Tracey W. Chan et al.
RNA editing, the endogenous modification of nucleic acids, is known to be altered in genes with important neurological function in schizophrenia (SCZ). However, the global profile and molecular functions of disease-associated RNA editing remain unclear. Here, we analyzed RNA editing in postmortem brains of four SCZ cohorts and uncovered a significant and reproducible trend of hypoediting in patients of European descent. We report a set of SCZ-associated editing sites via WGCNA analysis, shared across cohorts. Using massively parallel reporter assays and bioinformatic analyses, we observed that differential 3′ untranslated region (3′UTR) editing sites affecting host gene expression were enriched for mitochondrial processes. Furthermore, we characterized the impact of two recoding sites in the mitofusin 1 (MFN1) gene and showed their functional relevance to mitochondrial fusion and cellular apoptosis. Our study reveals a global reduction of editing in SCZ and a compelling link between editing and mitochondrial function in the disease.
Mudra Choudhury, Ting Fu, Kofi Amoah, Hyun-Ik Jun, Tracey W. Chan, Sungwoo Park, David W. Walker, Jae Hoon Bahn, Xinshu Xiao. Widespread RNA hypoediting in schizophrenia and its relevance to mitochondrial function. 2023-04-07. https://doi.org/10.1126/sciadv.ade9997
A plasmid-based 3′UTR MPRA tested both unedited A and edited G versions of 770 differential A-to-G RNA-editing sites drawn from four postmortem schizophrenia cohorts. Oligos carrying 158-nt test sequences were cloned into the eGFP 3′UTR, electroporated into HEK293 cells, and assayed by matched plasmid-DNA and mRNA sequencing 24 hours after transfection across three biological replicates.
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