Epigenetics of Muscle Development and Disease
Facioscapulohumeral muscular dystrophy (FSHD)
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy that indiscriminately affects males and females of all ages, with symptoms generally appearing in the second or third decade of life. The primary mediator of FSHD is the aberrant expression of the DUX4 gene from chromosome 4q35. The genetic criteria for FSHD are complex and ultimately merely permissive for disease; however, all forms of clinical FSHD exhibit epigenetic dysregulation of the 4q35 D4Z4 macrosatellite (Figure 1). Individuals genetically determined to have FSHD show a wide range of clinical severity, age of onset, and rate of disease progression, including some who remain asymptomatic throughout their lives. This variability suggests that the disease has a strong epigenetic component. We recently determined that asymptomatic individuals who meet the genetic criteria for FSHD have a more stable epigenetic repression of the contracted chromosome 4q35 D4Z4 array than clinically affected subjects with the same FSHD deletion, indicating that the key determinant for developing FSHD is the epigenetic status at 4q35. Thus, FSHD provides a natural model to investigate epigenetic mechanisms of gene regulation that function to repress gene expression in the healthy state and allow aberrant gene expression in the disease state. The epigenetic mechanisms differentially regulated in FSHD include DNA methylation, certain combinations of histone post-translational modifications, Polycomb Group proteins, chromatin remodeling machinery, lncRNAs, RNA dependent DNA methylation, and nuclear organization.
In addition, the severity of FSHD can be influenced by the functional status of numerous epigenetic modifiers of these mechanisms. Importantly, these epigenetic regulators, modifiers and mechanisms are all potential targets for FSHD therapeutic intervention (Figure 3).
Our FSHD projects include identifying the epigenetic regulators of the D4Z4 macrosatellite and DUX4 expression in myocytes from healthy and FSHD affected subjects, manipulating the epigenetic status of the array for potential therapeutic intervention, characterizing the epigenetics of DUX4 alternative mRNA splicing and developing reliable epigenetic tools for diagnosis.
For more information on FSHD epigenetics please see our recent review in Antioxidants & Redox Signaling.