title: Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways.
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation that results in aberrant expression of the transcription factor Double Homeobox 4 (DUX4). DUX4 protein is present in a small subset of FSHD muscle cells, making its detection and analysis of its effects historically difficult. Using a DUX4-activated reporter, we demonstrate the burst expression pattern of endogenous DUX4, its method of signal amplification in the unique shared cytoplasm of the myotube, and FSHD cell death that depends on its activation. Transcriptome analysis of DUX4-expressing cells revealed that DUX4 activation disrupts RNA metabolism including RNA splicing, surveillance and transport pathways. Cell signaling, polarity and migration pathways were also disrupted. Thus, DUX4 expression is sufficient for myocyte death, and these findings suggest mechanistic links between DUX4 expression and cell migration, supporting recent descriptions of phenotypic similarities between FSHD and an FSHD-like condition caused by FAT1 mutations.
authors.affiliation: Department of Pediatrics, Institute for Stem Cell and Regenerative Medicine and.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Rickard
authors.affiliation: Department of Pediatrics, Institute for Stem Cell and Regenerative Medicine and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Petek
authors.affiliation: Department of Pediatrics, Institute for Stem Cell and Regenerative Medicine and Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA dgmiller@uw.edu.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Miller
mesh_terms: D001692:Biological Transport; D016923:Cell Death; D002465:Cell Movement; D015870:Gene Expression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000378:metabolism* / Q000503:physiopathology; D012326:RNA Splicing
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins