Lymphocytes contribute to DUX4 target genes in FSHD muscle biopsies

Summary Facioscapulohumeral muscular dystrophy (FSHD) is an incurable myopathy linked to overexpression of DUX4. However, DUX4 is difficult to detect in FSHD myoblasts and target gene expression is not a consistent FSHD muscle biopsy biomarker, displaying efficacy only on pathologically inflamed samples. Immune gene misregulation occurs in FSHD muscle biopsies with DUX4 targets enriched for inflammatory processes. However, assessment of the FSHD immune cell transcriptome, and the evaluation of DUX4 and target gene expression has not yet been performed. We show that FSHD lymphoblastoid cell lines (LCLs) display robust DUX4 expression, and express early and late DUX4 targets. Moreover, genes elevated on FSHD LCLs are elevated in FSHD muscle biopsies, correlating with DUX4 target activation and histological inflammation. These genes are importantly unaltered in FSHD myoblasts/myotubes, implying a non-muscle source in biopsies. Our results indicate an immune cell source of DUX4 and target gene expression in FSHD muscle biopsies.