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Misexpression 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddz242","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T15:30:14Z","timestamp":1570203014000},"page":"3997-4011","source":"Crossref","is-referenced-by-count":37,"title":["DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double-stranded RNA foci in human cell models of FSHD"],"prefix":"10.1093","volume":"28","author":[{"given":"Sean C","family":"Shadle","sequence":"first","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"},{"name":"Molecular and Cellular Biology Program, University of Washington, Seattle, WA 91805, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean R","family":"Bennett","sequence":"first","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Jen","family":"Wong","sequence":"first","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy A","family":"Karreman","sequence":"first","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E","family":"Campbell","sequence":"first","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silv\u00e8re M","family":"van der Maarel","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda L","family":"Bass","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J","family":"Tapscott","sequence":"first","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,19]]},"reference":[{"key":"2020070810541638500_ref1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1001181","article-title":"Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene","volume":"6","author":"Snider","year":"2010","journal-title":"PLoS Genet."},{"key":"2020070810541638500_ref2","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/ng.3858","article-title":"DUX-family transcription factors regulate zygotic genome activation in placental mammals","volume":"49","author":"De Iaco","year":"2017","journal-title":"Nat. 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