Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Molecular Cell |
| Vol/bind | 82 |
| Udgave nummer | 9 |
| Sider (fra-til) | 1691-1707.e8 |
| ISSN | 1097-2765 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank Nadia L. Schmidt and Dorthe Riishøj for excellent technical assistance. Jérôme Rouvière and Søren Lykke-Andersen are thanked for discussion. Work in the T.H.J. laboratory was supported by the Danish National Research Council , the Lundbeck Foundation , and the Novo Nordisk Foundation (NNF). Work in the K.H. laboratory was supported by a center grant to the NNF Centre for Stem Cell Biology ( NNF17CC0027852 ), and through the Memorial Sloan Kettering Cancer Center Support Grant ( NIH P30 CA008748 ). Work in the A.S. laboratory was supported by grants from the NNF and the Lundbeck Foundation .
Funding Information:
We thank Nadia L. Schmidt and Dorthe Riishøj for excellent technical assistance. Jérôme Rouvière and Søren Lykke-Andersen are thanked for discussion. Work in the T.H.J. laboratory was supported by the Danish National Research Council, the Lundbeck Foundation, and the Novo Nordisk Foundation (NNF). Work in the K.H. laboratory was supported by a center grant to the NNF Centre for Stem Cell Biology (NNF17CC0027852), and through the Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748). Work in the A.S. laboratory was supported by grants from the NNF and the Lundbeck Foundation. W.G. A.S. K.H. and T.H.J. conceived the project. W.G. designed and performed the majority of experiments. I.M. performed the ChIP-seq experiments. M.W. M.S. and L.R. carried out computational analysis. K.I. contributed to experimental design and cell line generation. T.H.J. K.H. and A.S. supervised the project. W.G. and T.H.J. wrote the manuscript with input from all co-authors. K.H. is a co-founder of Dania Therapeutics, consultant for Inthera Bioscience AG, and scientific advisor for MetaboMed Inc. and Hannibal Innovation.
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© 2022 The Authors
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