Knopp, P;
Krom, YD;
Banerji, CRS;
Panamarova, M;
Moyle, LA;
den Hamer, B;
van der Maarel, SM;
(2016)
DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis.
J Cell Sci
, 129
(20)
pp. 3816-3831.
10.1242/jcs.180372.
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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.
| Type: | Article |
|---|---|
| Title: | DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/jcs.180372 |
| Publisher version: | https://doi.org/10.1242/jcs.180372 |
| Language: | English |
| Additional information: | © 2016. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell Biology, DUX4, DUX4C, FSHD, Stem Cells, Skeletal Muscle, Satellite Cell, Transcriptome, Facioscapulohumeral Muscular-Dystrophy, Abolishes Myoblast Differentiation, FSHD Muscle-Cells, Large Gene Lists, Satellite Cells, DNA Rearrangements, Candidate Gene, D4Z4, Expression, Protein |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1529614 |
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