Alu overexpression leads to increased double-stranded RNA in dermatomyositis

Dermatomyositis is an autoimmune condition characterized by a high interferon signature of unknown etiology. Because genes constitute only <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 and can form double-stranded (ds)RNA capable of triggering MDA5 leading to interferon production. We aligned muscle biopsy RNA sequencing data to the Telomere-to-Telomere reference genome and quantified short interspersed elements including Alus. Dermatomyositis muscle (n=39) showed a global elevation in Alu expression as well as an increased expression of unique Alu elements (n=557, p<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, with a hot spot of expression on chromosome 19. A subset of the uniquely overexpressed Alus (n=167) correlated strongly with interferon stimulated genes and markers of myositis activity. Since Alu transcripts have a propensity to form dsRNA and are the major targets of both ADAR and MDA5, we quantified the A-to-I RNA editomes inside Alus and found a uniquely expanded Alu editome in dermatomyositis compared to other myositis types, reflecting an increase in dsRNA. Edited Alus clustered on chromosome 19, which is known to have the highest concentration of dsRNA. 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.