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Background  The most common form of facioscapulohumeral muscular dystrophy (FSHD) is caused by a genetic contraction of the polymorphic D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q. In some studies, genes centromeric to the D4Z4 repeat array have been reported to be over-expressed in FSHD, including  FRG1  and  FRG2 , presumably due to decreased long-distance repression by the shorter array through a mechanism similar to position-effect variegation. Differential regulation of  FRG1  in FSHD has never been unequivocally proven, however,  FRG2  has been reproducibly shown to be induced in primary FSHD-derived muscle cells when differentiated  in vitro . The molecular function of FRG2 and a possible contribution to FSHD pathology remain unclear. Recent evidence has identified the mis-expression of  DUX4 , located within the D4Z4 repeat unit, in skeletal muscle as the cause of FSHD. DUX4 is a double homeobox transcription factor that has been shown to be toxic when expressed in muscle cells.    Methods  We used a combination of expression analysis by qRT/PCR and RNA sequencing to determine the transcriptional activation of  FRG2  and  DUX4.  We examined this in both differentiating control and FSHD derived muscle cell cultures or DUX4 transduced control cell lines. Next, we used ChIP-seq analysis and luciferase reporter assays to determine the potential DUX4 transactivation effect on the  FRG2  promoter.    Results  We show that DUX4 directly activates the expression of  FRG2 . Increased expression of FRG2 was observed following expression of DUX4 in myoblasts and fibroblasts derived from control individuals. Moreover, we identified DUX4 binding sites at the  FRG2  promoter by chromatin immunoprecipitation followed by deep sequencing and confirmed the direct regulation of DUX4 on the  FRG2  promoter by luciferase reporter assays. Activation of luciferase was dependent on both DUX4 expression and the presence of the DUX4 DNA binding motifs in the  FRG2  promoter.    Conclusion  We show that the FSHD-specific upregulation of  FRG2  is a direct consequence of the activity of DUX4 protein rather than representing a regional de-repression secondary to fewer D4Z4 repeats.

DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy