Abstract
Facioscapulohumeral dystrophy (FSHD) is the most frequent muscular disease in adults. FSHD is characterized by a weakness and atrophy of a specific set of muscles located in the face, the shoulder, and the upper arms. FSHD patients may present different genetic defects, but they all present epigenetic alterations of the D4Z4 array located on the subtelomeric part of chromosome 4, leading to chromatin relaxation and, ultimately, to the aberrant expression of one gene called DUX4. Once expressed, DUX4 triggers a cascade of deleterious events, eventually leading to muscle dysfunction and cell death. Here, we review studies on DUX4 expression in skeletal muscle to determine the genetic/epigenetic factors and regulatory proteins governing DUX4 expression, with particular attention to the different transcripts and their very low expression in muscle.
Highlights
Double homeobox 4 (DUX4) is a transcription factor that is normally expressed during embryonic development and in the human testes but suppressed in somatic tissue
The current review focuses on the recent understanding and regulation of DUX4 mRNA expression at the mRNA level in skeletal muscle and myogenic cells
In regard of the link between DUX4 expression and chromatin conformation, it was proposed that, as a single repeat, D4Z4 behaves as a CCCTC-binding factor (CTCF) insulator interfering with enhancer–promoter communication [37]
Summary
Double homeobox 4 (DUX4) is a transcription factor that is normally expressed during embryonic development and in the human testes but suppressed in somatic tissue (for review see [1]). In FSHD patients, DUX4 is aberrantly expressed in the muscle tissue [5,7]. The current review focuses on the recent understanding and regulation of DUX4 mRNA expression at the mRNA level in skeletal muscle and myogenic cells. FSHD is associated with genetic and epigenetic molecular changes of the D4Z4 microsatellite repeats in the subtelomeric region of chromosome 4 [12,13]. There are two different genetic mechanisms leading to FSHD, and both are associated with the loss of epigenetic marks within the D4Z4 and the aberrant expression of DUX4 [14]. There is3.aRceogunlsaetinosnuosf DinUtXh4eEsxcpireensstiiofinc community on DUX4 expression in FSHD biopsies, but its regulation still nTeheerdesistaocobnesednesucsipinhtehreesdci.enItnifidceceomd,mDunUitXy o4neDxUpXre4sesxipornessiisonreingFuSlHatDedbiobpysiesse, bvuetriatsl factors including D4reZg4ulaetpioingestnilel tniceemdsotdo ibfiecdaetcioipnh,ercehdr.oInmdoeesdo,mDUe Xc4onexfoprremssaiotnioins raengudlatthede bpyresesveenraclefoacftomrsyogenic enhancers (Fiingculurdein1g).D4Z4 epigenetic modification, chromosome conformation and the presence of myogenic enhancers (Figure 1). The four leading to the full-length protein (DUX4-fl) are pathogenic, whereas the one leading to a truncated protein (DUX4-s) is non-pathogenic
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