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

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 ADAR1 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 illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

Multiomic foundations of human prefrontal cortex tissue function

“…Knowledge of how living and postmortem human brain tissues differ at the molecular level is also of value for informing the design of studies that only utilize postmortem tissue. The LBP studies reported by Liharska et al 14 , Vornholt et al 17 , and Rodriguez de los Santos et al 49 characterized the differences in RNA transcript expression between living and postmortem human PFC tissues. By applying different analytic strategies to the same bulk RNA-seq data analyzed in those studies, as well as by integrating that data with genomic and proteomic data introduced here, the current report shows that differences exist between living and postmortem human brain samples with respect to (1) the expression levels of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression.…”