title: Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD.
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.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yvonne D
authors.initials: YD
authors.lastname: Krom
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thijssen
authors.forename: Janet M
authors.initials: JM
authors.lastname: Young
authors.forename: Bianca
authors.initials: B
authors.lastname: den Hamer
authors.forename: Judit
authors.initials: J
authors.lastname: Balog
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.forename: Lisa
authors.initials: L
authors.lastname: Maves
authors.forename: Lauren
authors.initials: L
authors.lastname: Snider
authors.forename: Paul
authors.initials: P
authors.lastname: Knopp
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
authors.forename: Tonnie
authors.initials: T
authors.lastname: Rijkers
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.forename: George W
authors.initials: GW
authors.lastname: Padberg
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D002843:Chromatin; C532958:Dux4 protein, mouse; D018398:Homeodomain Proteins