title: DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle.
abstract: Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed the expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of an unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that the expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Snider
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, ZA 2333, The Netherlands.
authors.forename: Judit
authors.initials: J
authors.lastname: Balog
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, ZA 2333, The Netherlands.
authors.forename: Richard J L F
authors.initials: RJ
authors.lastname: Lemmers
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, ZA 2333, The Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: Van Der Maarel
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA stapscot@fhcrc.org rabi_tawil@urmc.rochester.edu.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA Department of Neurology, University of Washington, Seattle, WA 98105, USA stapscot@fhcrc.org rabi_tawil@urmc.rochester.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D000328:Adult; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D017423:Sequence Analysis, RNA
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins