Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite at human chromosome 4q35. These deletions cause local chromatin changes and anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is part of a family of long noncoding RNAs (lncRNAs) expressed in skeletal muscle cells, with levels varying among patients. FRG2A localizes in the nucleolus and associates with repetitive DNA at ribosomal DNA (rDNA) loci and centromeres. Elevated FRG2A expression in FSHD cells alters the three-dimensional architecture of heterochromatin at the nucleolar periphery and reduces rDNA transcription and translation rates, resulting in decreased synthesis of skeletal muscle proteins. We also show that myoblasts from FSHD patients display reduced synthesis of skeletal muscle proteins during differentiation. Our results support a disease model in which nucleolar accumulation of D4Z4-driven lncRNA impairs protein synthesis and contributes to muscle wasting.