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Hum Mol Genet. 2014 Oct 15;23(20):5342-52. doi: 10.1093/hmg/ddu251. Epub 2014 May 26.

DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle.

Author information

1
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA.
2
Department of Human Genetics, Leiden University Medical Center, Leiden, ZA 2333, The Netherlands.
3
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA stapscot@fhcrc.org rabi_tawil@urmc.rochester.edu.
4
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA Department of Neurology, University of Washington, Seattle, WA 98105, USA stapscot@fhcrc.org rabi_tawil@urmc.rochester.edu.

Abstract

Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed the expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of an unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that the expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration.

PMID:
24861551
PMCID:
PMC4168822
DOI:
10.1093/hmg/ddu251
[Indexed for MEDLINE]
Free PMC Article

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