Abstract
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.
Highlights
Each unit of the D4Z4 macrosatellite repeat contains a copy of the DUX4 retrogene that encodes a double homeobox transcription factor [1,2,3,4]
We and others showed that facioscapulohumeral dystrophy (FSHD), a muscular dystrophy predominantly affecting facial and upper extremity muscles [7], is caused by D4Z4 repeat contraction-dependent (FSHD1) or –independent (FSHD2) chromatin relaxation in somatic tissues and low levels of DUX4 mRNA expression in skeletal muscle [5,8,9,10]
Generation of transgenic mouse models To determine whether the D4Z4 repeat with the DUX4 retrogene contains the regulatory elements necessary for germline expression and copy-number dependent somatic epigenetic repression, we generated two transgenic mouse lines
Summary
Each unit of the D4Z4 macrosatellite repeat contains a copy of the DUX4 retrogene that encodes a double homeobox transcription factor [1,2,3,4]. DUX4 is highly expressed in the germline and epigenetically repressed in most somatic tissues, including skeletal muscle [5,6]. We and others showed that facioscapulohumeral dystrophy (FSHD), a muscular dystrophy predominantly affecting facial and upper extremity muscles [7], is caused by D4Z4 repeat contraction-dependent (FSHD1) or –independent (FSHD2) chromatin relaxation in somatic tissues and low levels of DUX4 mRNA expression in skeletal muscle [5,8,9,10]. The polyadenylation (pA) site for DUX4 mRNA is in the DNA sequence immediately telomeric to the last D4Z4 repeat unit and chromosome 4 haplotypes non-permissive for FSHD contain inactivating polymorphisms at the pA site, explaining the haplotype-specificity of this disease [2,15,16]
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