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

William Garland, Iris Müller, Mengjun Wu, Manfred Schmid, Katsutoshi Imamura, Leonor Rib, Albin Sandelin, Kristian Helin*, Torben Heick Jensen*

*Corresponding author af dette arbejde

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Abstract

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.

OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind82
Nummer9
Sider (fra-til)1691-1707.e8
Antal sider26
ISSN1097-2765
DOI
StatusUdgivet - maj 2022

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