In Junk We Trust: Repetitive Dna, Epigenetics and Facioscapulohumeral Muscular Dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a peculiar etiology. Unlike most genetic disorders, FSHD is not caused by mutations in a protein-coding gene. Instead, it is associated with contraction of the D4Z4 macrosatellite repeat array located at 4q35. Interestingly, D4Z4 deletion is not sufficient per se to cause FSHD. Moreover, the disease severity, its rate of progression and the distribution of muscle weakness display great variability even among close family relatives. Hence, additional genetic and epigenetic events appear to be required for FSHD pathogenesis. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, exhibit alterations in the disease locus causing deregulation of 4q35 gene expression, ultimately leading to FSHD.

KEYWORDS::

• chromatin
• D4Z4 repeat
• DNA methylation
• epigenetics
• facioscapulohumeral muscular dystrophy
• FSHD
• ncRNA
• noncoding RNA
• repetitive DNA
• transcriptional repression

Acknowledgements

Owing to space limitations and to the fact that papers older than 5 years could not be cited, we apologize to our colleagues for the vastly incomplete documentation of their important contribution to facioscapulohumeral muscular dystrophy research. We thank Dr B Bodega, Dr V Orlando and Dr E Stupka for their critical reading of the manuscript.

Financial & competing interests disclosure

Research in Dr Davide Gabellini‘s laboratory is made possible by support provided by the European Research Council (ERC), the Muscular Dystrophy Association of USA (MDA), the European Network of Excellence in Alternative Splicing (EURASNET), the Association Francaise contre les Myopathies (AFM), the Jaya Motta private donation and the FSH Society, Inc. Davide Gabellini is a Dulbecco Telethon Institute Assistant Scientist. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Research in Dr Davide Gabellini‘s laboratory is made possible by support provided by the European Research Council (ERC), the Muscular Dystrophy Association of USA (MDA), the European Network of Excellence in Alternative Splicing (EURASNET), the Association Francaise contre les Myopathies (AFM), the Jaya Motta private donation and the FSH Society, Inc. Davide Gabellini is a Dulbecco Telethon Institute Assistant Scientist. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.