Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD
Publication year
2013Source
Plos Genetics, 9, 4, (2013), pp. e1003415ISSN
Publication type
Article / Letter to editor
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Organization
Neurology
Human Genetics
Journal title
Plos Genetics
Volume
vol. 9
Issue
iss. 4
Page start
p. e1003415
Subject
DCN MP - Plasticity and memory; DCN MP - Plasticity and memory NCEBP 10: Human Movement & FatigueAbstract
Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.
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- Academic publications [238441]
- Electronic publications [122544]
- Faculty of Medical Sciences [90373]
- Open Access publications [97535]
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