DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis
| Autor: | Louise A. Moyle, Christopher R. S. Banerji, Silvère M. van der Maarel, Paul Knopp, Maryna Panamarova, Bianca den Hamer, Peter S. Zammit, Yvonne D. Krom |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases Male Transcriptional Activation Satellite Cells Skeletal Muscle DUX4 Cellular differentiation Muscle Fibers Skeletal Skeletal muscle Apoptosis Mice Transgenic Stem cells 030105 genetics & heredity Biology Muscle Development Transcriptome Myoblasts 03 medical and health sciences medicine Myocyte Facioscapulohumeral muscular dystrophy Animals Humans Regeneration Epigenetics 10. No inequality Muscle Skeletal Molecular Biology Cell Shape Homeodomain Proteins FSHD Myogenesis Cell Differentiation Cell Biology medicine.disease Molecular biology Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure DUX4c Satellite cell Developmental Biology Research Article |
| Zdroj: | Journal of Cell Science, 129(20), 3816-3831 Journal of Cell Science Knopp, P, Krom, Y D, Banerji, C R S, Panamarova, M, Moyle, L A, den Hamer, B, van der Maarel, S M & Zammit, P S 2016, ' DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis ', Journal of Cell Science, vol. 129, no. 20, pp. 3816-3831 . https://doi.org/10.1242/jcs.180372 |
| DOI: | 10.1242/jcs.180372 |
| Popis: | 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. Summary: DUX4 underlies pathogenesis in facioscapulohumeral muscular dystrophy. DUX4 acts mainly as a transcriptional activator that inhibits myogenesis by orchestrating a gene expression profile representative of a more stem-cell-like state. |
| Databáze: | OpenAIRE |
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