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Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. The condition is linked to hypomethylation of the D4Z4 macrosatellite repeat at chromosome 4q35, leading to epigenetic derepression of the transcription factor DUX4; coupled with a permissive 4qA haplotype supplying a poly(A) signal. DUX4 may drive FSHD pathology via both induction of target genes and inhibition of the function of the myogenic master regulator PAX7. Biomarkers for FSHD have focused on DUX4 target gene expression. We have, however, reported that PAX7 target gene repression is a hallmark of FSHD skeletal muscle. Here we demonstrate that PAX7 target gene repression is an equivalent biomarker to DUX4 target gene expression when considering RNA-Sequencing data from magnetic resonance imaging-guided muscle biopsies. Moreover, PAX7 target gene repression correlates with active disease, independent to DUX4 target gene expression. PAX7 target genes are also repressed in RNA-Sequencing data from single cells, representing a significantly better biomarker of FSHD cells than DUX4 target gene expression. Importantly, PAX7 target gene repression is a significant biomarker in the majority of FSHD cells that are DUX4 target gene negative, and on which the DUX4 biomarker is indiscriminate. To facilitate the evaluation of validated biomarkers we provide a simple tool that outputs biomarker values from a normalized expression data matrix. In summary, PAX7 target gene repression in FSHD correlates with disease severity, independently of DUX4 target gene expression. At the single-cell level, PAX7 target gene repression can efficiently discriminate FSHD cells, even when no DUX4 target genes are detectable.

human molecular genetics online/human molecular genetics

PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level