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DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double-stranded RNA foci in human cell models of FSHD.

Authors
  • Shadle, Sean C1, 2
  • Bennett, Sean R1
  • Wong, Chao-Jen1
  • Karreman, Nancy A1
  • Campbell, Amy E1
  • van der Maarel, Silvère M3
  • Bass, Brenda L4
  • Tapscott, Stephen J1
  • 1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • 2 Molecular and Cellular Biology Program, University of Washington, Seattle, WA 91805, USA.
  • 3 Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands. , (Netherlands)
  • 4 Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA.
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
Dec 01, 2019
Volume
28
Issue
23
Pages
3997–4011
Identifiers
DOI: 10.1093/hmg/ddz242
PMID: 31630170
Source
Medline
Language
English
License
Unknown

Abstract

The DUX4 transcription factor is normally expressed in the cleavage-stage embryo and regulates genes involved in embryonic genome activation. 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. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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