Cis and trans modifiers in facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic repression of the D4Z4 repeat resulting in misexpression of the repeat-encoded DUX4 gene in skeletal muscle. Two mechanisms are known to drive this D4Z4 epigenetic dysregulation: a contraction of the D4Z4 repeat or mutations in DNMT3B or SMCHD1, both epigenetic regulators of the repeat that are responsible for the establishment or maintenance of the repeat’s epigenetic repressive state in somatic cells. However, the aforementioned (epi)genetic changes lead to FSHD only if the individual also has a disease-permissive D4Z4 allele which allows for stable DUX4 expression in skeletal muscle. This disease permissivity of D4Z4 alleles has been attributed to the presence of a DUX4 polyadenylation signal adjacent to the D4Z4 repeat which is used for transcription termination. Despite knowing the root cause of FSHD, to date, there is no curative therapy available for FSHD and in some cases, the genetic etiology of the disease remains unknown. In this thesis, we identified a new FSHD disease gene called LRIF1 and performed its follow-up functional studies in human somatic cells and mouse embryonic stem cells. In addition, we also pursued a new targeted gene therapy for FSHD by employing CRISPR-based mutagenesis of the DUX4 polyadenylation signal.