Cytosine-to-uracil RNA editing is upregulated by pro-inflammatory stimulation of myeloid cells

Abstract

Myeloid cells undergo large changes to their gene expression profile in response to inflammatory stimulation. This includes an increase in post-transcriptional modifications carried out by adenosine-to-inosine (A-to-I) and cytosine-to-uracil (C-to-U) RNA editing enzymes. However, the precise RNA editing targets altered by stimulation and the consequences of RNA editing on gene expression and the proteome have been understudied. We present a comprehensive RNA editing analysis of stimulated myeloid cells across three independent cohorts totalling 297 samples, including monocytes and IPS-derived microglia. We observed that C-to-U editing, while less abundant, has a higher effect size in response to stimulation than A-to-I, and has a greater potential to recode the proteome. We investigated the consequences of RNA editing on RNA stability and gene expression using in silico and in vitro reporter methods, and identified a recoding C-to-U site in ARSB that mimics a reported lysosomal storage disorder mutation.