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Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

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  • William Garland
  • Iris Müller, University of Copenhagen, Memorial Sloan-Kettering Cancer Center
  • ,
  • Mengjun Wu, University of Copenhagen, Karolinska Institutet
  • ,
  • Manfred Schmid
  • ,
  • Katsutoshi Imamura
  • Leonor Rib, University of Copenhagen
  • ,
  • Albin Sandelin, University of Copenhagen
  • ,
  • Kristian Helin, University of Copenhagen, Memorial Sloan-Kettering Cancer Center
  • ,
  • Torben Heick Jensen

Transposable elements (TEs) are widespread genetic parasites known to be kept under tight transcriptional control. Here, we describe a functional connection between the mouse-orthologous “nuclear exosome targeting” (NEXT) and “human silencing hub” (HUSH) complexes, involved in nuclear RNA decay and the epigenetic silencing of TEs, respectively. Knocking out the NEXT component ZCCHC8 in embryonic stem cells results in elevated TE RNA levels. We identify a physical interaction between ZCCHC8 and the MPP8 protein of HUSH and establish that HUSH recruits NEXT to chromatin at MPP8-bound TE loci. However, while NEXT and HUSH both dampen TE RNA expression, their activities predominantly affect shorter non-polyadenylated and full-length polyadenylated transcripts, respectively. Indeed, our data suggest that the repressive action of HUSH promotes a condition favoring NEXT RNA decay activity. In this way, transcriptional and post-transcriptional machineries synergize to suppress the genotoxic potential of TE RNAs.

Original languageEnglish
JournalMolecular Cell
Pages (from-to)1691-1707.e8
Number of pages26
Publication statusPublished - May 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors

    Research areas

  • HUSH complex, NEXT complex, retrotransposons, RNA decay, RNA exosome, transposable elements

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