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Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating muscle disease that currently does not have an effective cure or therapy. The abnormal reactivation of  DUX4 , an embryonic gene that is epigenetically silenced in somatic tissues, is causal to FSHD. Disease-specific reactivation of  DUX4  has two common characteristics, the presence of a non-canonical polyadenylation sequence within exon 3 of  DUX4  that stabilizes pathogenic transcripts, and the loss of repressive chromatin modifications at D4Z4, the macrosatellite repeat which encodes  DUX4 . We used CRISPR/Cas9 to silence  DUX4  using two independent approaches. We deleted the  DUX4  pathogenic polyadenylation signal, which resulted in downregulation of pathogenic  DUX4-fl  transcripts. In another approach, we transcriptionally repressed  DUX4  by seeding heterochromatin using the dCas9-KRAB platform within exon 3. These feasibility of targeting  DUX4  experiments were initially tested in a non-myogenic carcinoma cell line that we have previously characterized. Subsequently, in an immortalized patient myoblast cell line, we demonstrated that targeting  DUX4  by either approach led to substantial downregulation of not only pathogenic  DUX4  transcripts, but also a subset of its target genes that are known biomarkers of FSHD. These findings offer proof-of-concept of the effect of silencing the polyadenylation sequence on pathogenic  DUX4  expression.

CRISPR mediated targeting of DUX4 distal regulatory element represses DUX4 target genes dysregulated in Facioscapulohumeral muscular dystrophy