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

Abstract

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.