RT Journal Article
SR Electronic
T1 DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double stranded RNA foci in human cell models of FSHD
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 734541
DO 10.1101/734541
A1 Sean C. Shadle
A1 Sean R. Bennett
A1 Chao-Jen Wong
A1 Nancy A. Karreman
A1 Amy E. Campbell
A1 Silvère M. van der Maarel
A1 Brenda L. Bass
A1 Stephen J. Tapscott
YR 2019
UL http://biorxiv.org/content/early/2019/08/13/734541.abstract
AB The DUX4 transcription factor is normally expressed in the cleavage stage embryo and regulates genes involved in embryonic genome activation. Mis-expression of DUX4 in skeletal muscle, however, is toxic and causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity is due, in part, to the activation of the double-stranded RNA (dsRNA) response pathway and the accumulation of intranuclear dsRNA foci. Here, we determined the composition of DUX4-induced dsRNAs. We found that a subset of DUX4-induced dsRNAs originate from inverted Alu repeats embedded within the introns of DUX4-induced transcripts and from DUX4-induced dsRNA-forming intergenic transcripts enriched for endogenous retroviruses, Alu and LINE-1 elements. However, these repeat classes were also represented in dsRNAs from cells not expressing DUX4. In contrast, pericentric human satellite II (HSATII) repeats formed a class of dsRNA specific to the DUX4 expressing cells. Further investigation revealed that DUX4 can initiate the bidirectional transcription of normally heterochromatin-silenced HSATII repeats. DUX4 induced HSATII RNAs co-localized with DUX4-induced nuclear dsRNA foci and with intranuclear aggregation of EIF4A3 and ADAR1. Finally, gapmer-mediated knockdown of HSATII transcripts depleted DUX4-induced intranuclear ribonucleoprotein aggregates and decreased DUX4-induced cell death, suggesting that HSATII formed dsRNAs contribute to DUX4 toxicity.