Efthymiou, A. G. | Search bioRxiv

bioRxiv2025

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

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.

genomics↗

bioRxiv2019

Integration of Alzheimer’s disease genetics and myeloid cell genomics identifies novel causal variants, regulatory elements, genes and pathways

Genome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimers disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD.

genomics↗