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

Area of Science:

• Genomics
• Immunology
• Molecular Biology

Background:

• Dermatomyositis is an autoimmune disease with a high interferon signature of unknown cause.
• The non-coding genome, including abundant Alu elements, plays a potential role in disease pathogenesis.
• Alu elements can form double-stranded RNA (dsRNA), activating MDA5 and leading to interferon production.

Purpose of the Study:

• To investigate the role of Alu elements and their expression in dermatomyositis.
• To explore the relationship between Alu expression, RNA editing, and interferon signatures in dermatomyositis.

Main Methods:

• Analyzed muscle biopsy RNA sequencing data from dermatomyositis patients and healthy controls.
• Quantified expression of short interspersed elements, including Alus, and A-to-I RNA editing.
• Correlated Alu expression and editing patterns with interferon-stimulated genes and disease activity markers.

Main Results:

• Dermatomyositis muscle tissue showed significantly elevated global and unique Alu element expression compared to controls.
• Overexpressed Alus, particularly inverted repeat types, were found outside of coding genes and correlated with disease activity.
• A unique expansion of Alu A-to-I editing was observed, indicating increased dsRNA, with edited Alus clustering on chromosome 19.

Conclusions:

• Hypothesize that overexpressed Alus in dermatomyositis generate endogenous dsRNA that overwhelms RNA editing capacity.
• This dsRNA triggers innate immune sensors, leading to the characteristic interferon signature in dermatomyositis.
• Suggests a novel pathogenic mechanism driven by non-coding repetitive elements in autoimmune disease.