title: DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy.
abstract: Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of DUX4 in skeletal muscle cells. DUX4 is a transcription factor that activates genes normally associated with stem cell biology and its mis-expression in FSHD cells results in apoptosis. To identify genes and pathways necessary for DUX4-mediated apoptosis, we performed an siRNA screen in an RD rhabdomyosarcoma cell line with an inducible DUX4 transgene. Our screen identified components of the MYC-mediated apoptotic pathway and the double-stranded RNA (dsRNA) innate immune response pathway as mediators of DUX4-induced apoptosis. Further investigation revealed that DUX4 expression led to increased MYC mRNA, accumulation of nuclear dsRNA foci, and activation of the dsRNA response pathway in both RD cells and human myoblasts. Nuclear dsRNA foci were associated with aggregation of the exon junction complex component EIF4A3. The elevation of MYC mRNA, dsRNA accumulation, and EIF4A3 nuclear aggregates in FSHD muscle cells suggest that these processes might contribute to FSHD pathophysiology.
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, United States of America.|Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Shadle
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jun Wen
authors.identifier: 0000-0001-8033-7866
authors.initials: JW
authors.lastname: Zhong
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Amy E
authors.identifier: 0000-0001-6513-5836
authors.initials: AE
authors.lastname: Campbell
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Melissa L
authors.identifier: 0000-0003-0151-4997
authors.initials: ML
authors.lastname: Conerly
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagannathan
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Chao-Jen
authors.initials: CJ
authors.lastname: Wong
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Morello
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Stephen J
authors.identifier: 0000-0002-0319-0968
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000235:genetics; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics; D005091:Exons; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012330:RNA, Double-Stranded / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D039601:Eukaryotic Initiation Factor-4A; D020169:Caspases; C403493:EIF4A3 protein, human; D053487:DEAD-box RNA Helicases