DUX4 activates common and context-specific intergenic transcripts and isoforms
Dongxu Zheng (Leiden University Medical Center)
Anita van den Heuvel (Leiden University Medical Center)
Judit Balog (Leiden University Medical Center)
Iris M. Willemsen (Leiden University Medical Center)
Susan Kloet (Leiden University Medical Center)
Stephen J. Tapscott (University of Washington, Fred Hutchinson Cancer Research Center)
Ahmed Mahfouz (Leiden University Medical Center, TU Delft - Pattern Recognition and Bioinformatics)
Silvère M. van der Maarel (Leiden University Medical Center)
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Abstract
DUX4 regulates the expression of genic and nongenic elements and modulates chromatin accessibility during zygotic genome activation in cleavage stage embryos. Its misexpression in skeletal muscle causes facioscapulohumeral dystrophy (FSHD). By leveraging full-length RNA isoform sequencing with short-read RNA sequencing of DUX4-inducible myoblasts, we elucidate an isoform-resolved transcriptome featuring numerous unannotated isoforms from known loci and novel intergenic loci. While DUX4 activates similar programs in early embryos and FSHD muscle, the isoform usage of known DUX4 targets is notably distinct between the two contexts. DUX4 also activates hundreds of previously unannotated intergenic loci dominated by repetitive elements. The transcriptional and epigenetic profiles of these loci in myogenic and embryonic contexts indicate that the usage of DUX4-binding sites at these intergenic loci is influenced by the cellular environment. These findings demonstrate that DUX4 induces context-specific transcriptomic programs, enriching our understanding of DUX4-induced muscle pathology.