Alu Overexpression Leads to an Increased Double‐stranded RNA Signature in Dermatomyositis

Objective Dermatomyositis is an autoimmune condition characterized by a high interferon signature of unknown etiology. Because coding sequences constitute <1.2% of our genomes, there is a need to explore the role of the non‐coding genome in disease pathogenesis. Our genomes include roughly 1.2 million Alu elements occupying about 10% of the genome, which can form double‐stranded (ds)RNA capable of triggering MDA5 leading to interferon production. Methods We aligned muscle biopsy RNA sequencing data to the Telomere‐to‐Telomere reference genome and quantified short interspersed elements including Alus. Since Alus have a propensity to form dsRNA and are the major targets of both ADAR and MDA5, we quantified A‐to‐I RNA editing, which reflects dsRNA in vivo. Results Dermatomyositis muscle (n=39) showed a global elevation in Alu expression (including inverted repeat Alus with high potential to form dsRNA), as well as an increased expression of unique Alu elements (n=557, q<0.05) compared to healthy controls (n=34), in a pattern not seen in other myositis types (n=81). The majority (75.3%) of these Alus originated from genomic regions outside genes. A cluster of the uniquely overexpressed Alus (n=167) correlated with interferon stimulated genes and markers of myositis activity. Additionally, we found a uniquely expanded Alu A‐to‐I editome in dermatomyositis, reflecting an increase in dsRNA. Edited Alus clustered on chromosome 19, which is known to have the highest concentration of dsRNA. Conclusion We hypothesize that overexpressed Alus in dermatomyositis form endogenous dsRNA that exceed the capacity of RNA editing enzymes and trigger dsRNA sensors leading to interferon production.