Facioscapulohumeral muscular dystrophy (FSHD) is associated with contraction of D4Z4 repeats on chromosome 4, loss of repressive polycomb-mediated chromatin modifications and derepression of nearby genes. Now, Davide Gabellini and colleagues identify a long RNA produced from the contracted D4Z4 locus and show that it has a role in epigenetic dysregulation in FSHD (Cell 149, 819–831, 2012). The authors show that a transcript called DBE-T is produced from the D4Z4 repeat in primary muscle cells from individuals with FSHD but not from healthy controls. They used rodent cells containing a single human chromosome 4 to show that DBE-T is localized within the nucleus at the D4Z4 locus and that it binds to the trithorax group protein Ash1L. They also showed that ASH1L protein localizes to the FSHD locus and is more abundant in primary muscle cells from individuals with FSHD compared to those from healthy controls. The authors suggest a model in which contraction of D4Z4 repeats causes loss of polycomb silencing and inappropriate production of DBE-T, thereby leading to recruitment of ASH1L, chromatin remodeling and derepression of nearby genes in FSHD.