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

doi:10.1016/j.molcel.2022.03.004

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 for this work

Department of Molecular Biology and Genetics - RNA Biology and Innovation

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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.

Original language	English
Journal	Molecular Cell
Volume	82
Issue	9
Pages (from-to)	1691-1707.e8
Number of pages	26
ISSN	1097-2765
DOIs	https://doi.org/10.1016/j.molcel.2022.03.004
Publication status	Published - May 2022

Keywords

HUSH complex
NEXT complex
retrotransposons
RNA decay
RNA exosome
transposable elements

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1-s2.0-S1097276522002131-mainFinal published version, 4.87 MBLicence: CC BY

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

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.",

keywords = "HUSH complex, NEXT complex, retrotransposons, RNA decay, RNA exosome, transposable elements",

author = "William Garland and Iris M{\"u}ller and Mengjun Wu and Manfred Schmid and Katsutoshi Imamura and Leonor Rib and Albin Sandelin and Kristian Helin and Jensen, {Torben Heick}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

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doi = "10.1016/j.molcel.2022.03.004",

language = "English",

volume = "82",

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Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression. / Garland, William; Müller, Iris; Wu, Mengjun et al.
In: Molecular Cell, Vol. 82, No. 9, 05.2022, p. 1691-1707.e8.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

AU - Garland, William

AU - Müller, Iris

AU - Wu, Mengjun

AU - Schmid, Manfred

AU - Imamura, Katsutoshi

AU - Rib, Leonor

AU - Sandelin, Albin

AU - Helin, Kristian

AU - Jensen, Torben Heick

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - HUSH complex

KW - NEXT complex

KW - retrotransposons

KW - RNA decay

KW - RNA exosome

KW - transposable elements

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DO - 10.1016/j.molcel.2022.03.004

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SN - 1097-2765

VL - 82

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JO - Molecular Cell

JF - Molecular Cell

IS - 9

ER -

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

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