A novel family of lncRNAs relate facioscapulohumeral muscular dystrophy to nucleolar architecture and protein synthesis

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite repeats at human chromosome 4q35. These deletions accompany local chromatin changes and the anomalous expression of nearby transcriptsFRG2A, DBET,andD4Z4.We discovered thatFRG2Ais one member of a family of long non-coding RNAs (lncRNAs) expressed at elevated levels in skeletal muscle cells with distinct amounts detected in individual patients. We found thatFRG2AlncRNA preferentially associates with rDNA sequences and centromeres and promotes the three-dimensional association of centromeres with the nucleolar periphery in FSHD cells. Furthermore, we demonstrate that the elevatedFRG2Aexpression in cells from FSHD patients reduces rDNA transcription and global protein synthesis. Our results frame an entirely unanticipated new disease model in which elevated lncRNAs levels mediated by deletions of D4Z4 macrosatellite repeats leads to a diminished protein synthesis capacity, thereby contributing to muscle wasting.