Inappropriate gene activation in FSHD: A repressor complex binds a chromosomal repeat deleted in dystrophic muscle

Facioscapulohumeral muscular dystrophy (FSHD), a common myopathy, is an autosomal dominant disease of unknown molecular mechanism. Almost all FSHD patients carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Here, we find that in FSHD muscle 4q35 genes located upstream of D4Z4 are inappropriately over-expressed. We show that an element within D4Z4 specifically binds a multi-protein complex consisting of YY1, a known transcriptional repressor, HMGB2, an architectural protein, and nucleolin. We demonstrate that this multi-protein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. Based upon these results we propose that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes resulting in disease.