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 noncoding genome in disease pathogenesis. Our genomes include roughly 1.2 million Alu elements occupying approximately 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. Because Alus have a propensity to form dsRNA and are the major targets of both adenosine deaminase RNA specific and MDA5, we quantified adenosine to inosine (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 with healthy controls (n = 34), in a pattern not seen in other myositis types (n = 81). Most (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 exceeds the capacity of RNA editing enzymes and triggers dsRNA sensors leading to interferon production.