FSHD

28 March 2019
Parallel-1
28-AM-Parallel-1 11:00 > 12:30 FSHD Amphi A


11:00 S16-01 Facioscapulohumeral muscular dystrophy > S. Silvere VAN DER MAAREL (Leiden, Netherlands)
Objectives : Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited myopathies clinically defined by progressive weakness and wasting of the facial, shoulder girdle and upper arm muscles. With disease progression, other muscles may become affected too. Non-muscular features are rare, and often subclinical. FSHD is associated with inappropriate expression of the cleavage stage transcription factor DUX4 as a consequence of partial chromatin relaxation of the D4Z4 repeat on chromosome 4q35. The D4Z4 repeat varies between 8-100 units in the population and adopts a repressive chromatin structure in somatic cells such as skeletal muscle. As a result of D4Z4 repeat contractions to a size of 1-10 units (FSHD1), or mutations in chromatin modifiers that facilitate a repressive D4Z4 chromatin structure in somatic cells (FSHD2), in FSHD muscle the D4Z4 chromatin structure is more relaxed. This causes derepression of the D4Z4-embedded DUX4 retrogene in skeletal muscle, which, in turn, initiates a cascade of events leading to muscle damage.
Most FSHD2 patients have a heterozygous mutation in SMCHD1 encoding a chromatin repressor that binds to D4Z4. Reduced SMCHD1 repressor activity at D4Z4 causes DUX4 expression in skeletal muscle. SMCHD1 was also identified as a modifier for FSHD1 and a recent FSHD population study suggests that, rather than separate entities, FSHD1 and FSHD2 form a continuum in which genetic (the repeat size) and epigenetic (the activity of D4Z4 chromatin modifiers) synergistically contribute to DUX4 derepression and disease presentation.
Only a minority of myonuclei express DUX4 in FSHD muscle cell cultures. How such sporadic expression leads to severe muscle wasting in FSHD largely remains unclear. Indeed transcriptome studies in FSHD have systematically been challenged by the sporadic nature of DUX4 expression, with the majority of non-affected cells masking the consequences of the presence of DUX4. Taking advantage of single-cell RNA-sequencing, comb
11:30 S16-02 Applying genome-wide CRISPR screens for therapeutic discovery in FSHD > A. Angela LEK (New Haven, Usa) 12:00 S16-03 PAX7, DUX4 and Facioscapulohumeral muscular dystrophy > P. Peter ZAMMIT (London, United Kingdom)
Objectives : Skeletal muscle is an archetypal adult stem cell model, in which maintenance, growth and repair of functionally specialised post-mitotic cells is achieved by recruitment of undifferentiated precursors. For the past 18 years, my core research has been directed at understanding how muscle stem cells are regulated in healthy, aged and diseased skeletal muscle. The functional unit of skeletal muscle is the myofibre: a giant syncytial cell maintained by hundreds of post-mitotic myonuclei. The routine needs for myonuclear homeostasis, together with the more sporadic demands for hypertrophy and repair, are performed by muscle satellite cells. These resident stem cells are normally mitotically quiescent in mature muscle, and so must first be activated to undergo extensive proliferation to generate myoblasts that eventually differentiate to provide new myonuclei.


The main themes of the group at King’s College London currently include investigating the transcriptional and signaling control of satellite cell activation and cell fate choice, and examining pathomechanisms and potential therapies for Emery-Dreifuss muscular dystrophy, Fascioscapulohumeral muscular dystrophy and rhabdomyosarcoma.

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