Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression
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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; Schmid, Manfred; Imamura, Katsutoshi; Rib, Leonor; Sandelin, Albin; Helin, Kristian; Jensen, Torben Heick.
In: Molecular Cell, Vol. 82, No. 9, 2022, p. 1691-1707.e8.Research output: Contribution to journal › Journal article › peer-review
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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
N1 - Publisher Copyright: © 2022 The Authors
PY - 2022
Y1 - 2022
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
U2 - 10.1016/j.molcel.2022.03.004
DO - 10.1016/j.molcel.2022.03.004
M3 - Journal article
C2 - 35349793
AN - SCOPUS:85129247825
VL - 82
SP - 1691-1707.e8
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 9
ER -
ID: 307329428