title: DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis.
abstract: Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenic mice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK.
authors.forename: Paul
authors.identifier: 0000-0003-4356-1927
authors.initials: P
authors.lastname: Knopp
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Postbus 9600, 2300 RC, The Netherlands.
authors.forename: Yvonne D
authors.initials: YD
authors.lastname: Krom
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK Centre of Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Christopher R S
authors.initials: CR
authors.lastname: Banerji
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK.
authors.forename: Maryna
authors.initials: M
authors.lastname: Panamarova
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Moyle
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Postbus 9600, 2300 RC, The Netherlands.
authors.forename: Bianca
authors.initials: B
authors.lastname: den Hamer
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Postbus 9600, 2300 RC, The Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK peter.zammit@kcl.ac.uk.
authors.forename: Peter S
authors.identifier: 0000-0001-9562-3072
authors.initials: PS
authors.lastname: Zammit
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D048430:Cell Shape / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
chemical_list: C121257:DUX4L1 protein, human; C532958:Dux4 protein, mouse; D018398:Homeodomain Proteins
keywords: DUX4; DUX4c; FSHD; Satellite cell; Skeletal muscle; Stem cells; Transcriptome