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.

R.N., A.M. declare no competing interests. T.M. reports consulting fees from Bristol-Myers Squibb, Cugene, Miro Bio, Rome Therapeutics, Evolved, and Codify. He serves on the Scientific Advisory Board of Rome Therapeutics, the Tri-Institutional Drug Discovery Institute (non-profit), and the University of Copenhagen LEO Skin Immunology Centre (non-profit).

This study is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (grant K08AR082939)

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE220915

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes