Epigenomic Studies of Facioscapulohumeral Muscular Dystrophy (FSHD)

Abstract

Most cases of Facioscapulohumeral Muscular Dystrophy (FSHD) are linked to a repeat number contraction of D4Z4 sequences in the subtelomeric region of chromosome 4q (4qter), so‐called “4q‐linked” FSHD. However, the role of the D4Z4 repeats and molecular consequences of their contraction in the disease are still unclear. With chromatin crosslinking and immunoprecipitation (ChIP), we found that histone H3 lysine 9 trimethylation (H3K9me3), which is present in normal cells’ D4Z4, is lost in FSHD. This epigenetic change was also observed in the rare FSHD cases with no detectable D4Z4 contraction (i.e., phenotypic FSHD), but not in other muscular dystrophies. The H3K9me3 modification on other repeat sequences we studied remains intact in FSHD. These data suggest that H3K9me3 loss at 4qter D4Z4 can serve as a faithful diagnostic marker for FSHD, and that FSHD is a disease with “epigenetic abnormality”. We identified HP1γ and cohesin recruitment by H3K9me3 to D4Z4 in a cell type‐specific manner in normal cells. This binding is lost in FSHD, which may be related to the muscle‐specific pathogenesis of the disease. Furthermore, cohesin plays an active role in HP1γ recruitment to D4Z4. We hypothesize that heterochromatic D4Z4 repeats spread a silencing chromatin structure to other genomic regions through HP1γ/cohesin‐mediated long‐distance chromatin interactions. D4Z4 heterochromatin is disrupted in FSHD, which may deregulate downstream target genes resulting in muscular dystrophy.