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

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

doi:10.1016/j.molcel.2022.03.004

Cited by 54 publications

(57 citation statements)

References 101 publications

(183 reference statements)

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“…Silencing of the 2C transcriptional program involves redundant but rather independent mechanisms, including transcriptional repression of the Dux gene by TRIM66, the E3 ligase PIAS4 or SMCHD1 as well as physical recruitment of Dux loci to nucleolar heterochromatin [11][12][13][14] . Furthermore, MERVL repeats are transcriptionally silenced by the protein complex ZMYM2/LSD1 or the chromatin remodeler CAF-1 and post-transcriptionally by the RNA decay complex NEXT [15][16][17] . However, whether a direct DUX-dependent negative feedback loop mechanism ensures a timed and irreversible silencing of the 2C-associated transcriptional program remains unknown.…”

Section: Introductionmentioning

confidence: 99%

The homeobox transcription factor DUXBL controls exit from totipotency

Vega-Sendino

Olbrich

Stein

et al. 2022

Preprint

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Upon exit from the totipotent 2-cell (2C) embryo stage, the 2C-associated transcriptional program needs to be efficiently silenced. However, the molecular mechanisms involved in this process remain mostly unknown. Here, we demonstrate that the 2C-specific transcription factor DUX directly induces the expression of DUXBL to promote this silencing. Indeed, DUX expression in Duxbl-knockout ESC causes increased induction of the 2C-transcriptional program, whereas DUXBL overexpression impairs 2C-associated transcription. CUT&RUN analyses show that DUXBL gains accessibility to DUX-bound regions in DUX-induced ESC while it is unable to bind those regions in uninduced cells. Mechanistically, we determined that DUXBL interacts with TRIM24 and TRIM33, two members of the tripartite motif superfamily involved in gene silencing and co-localizes with them in nuclear foci upon DUX expression. Furthermore, DUXBL downregulation in mouse zygotes leads to a penetrant 2C-stage arrest. Our data reveals an unexpected role for DUXBL in controlling the exit from totipotency.

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Section: Introductionmentioning

confidence: 99%

The homeobox transcription factor DUXBL controls exit from totipotency

Vega-Sendino

Olbrich

Stein

et al. 2022

Preprint

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“…Furthermore, epigenetic silencing by the HUSH complex also mediates position-effect variegation in human cells [ 37 ]. Recently, a study described a functional connection between the mouse-orthologous “nuclear exosome targeting” (NEXT) and HUSH complexes, involved in nuclear RNA decay and the epigenetic silencing of TEs, respectively, suggesting that transcriptional and post-transcriptional machineries synergize to suppress the genotoxic potential of TE RNAs [ 38 ]. H3K9me3 reader proteins, such as HP1, can bind to pre-existing H3K9me3 and bridge with SETDB1 through direct interaction [ 39 ].…”

Section: Silencing and Transcriptional Regulation Of Ervsmentioning

confidence: 99%

Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases

Zhang

Pan

Cong

et al. 2022

IJMS

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Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases.

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“…HUSH has been implicated in the silencing of TEs, with a strong impact on LINE-1 expression [103,105,131,132]. Recent evidence from the mouse system reveals a synergy mechanism of transcriptional silencing of LINE-1s by HUSH and their post-transcriptional silencing by the nuclear exosome targeting (NEXT) complex [133,134]. The NEXT complex is an activator of the exosome complex that is one of the major RNA degradation machineries in mammalian cells degrading RNA in the 3 0 ?…”

Section: In the Cytoplasm: Poly(a) Tails Uridylation Rnp Sequestratio...mentioning

confidence: 99%

“…The NEXT complex consists of three protein subunits: ZCCHC8, RBM7 and MTR4, and it has been implicated in the clearance of short-lived products of pervasive transcription in the nucleus [128]. Motivated by the early finding of RBM7-binding TE transcripts in HeLa cells [135], Garland et al [133] created ZCCHC8 knock-out mouse ES cells and observed the accumulation of RNA of LINE-1 and other TEs. Similar observations were made in MPP8 and double ZCCHC8 and MPP8 knock-out cells and in conditional auxin-induced degron cell lines but with no apparent additive effects of double knock-out.…”

Section: In the Cytoplasm: Poly(a) Tails Uridylation Rnp Sequestratio...mentioning

confidence: 99%

An update on post‐transcriptional regulation of retrotransposons

Warkocki

2022

FEBS Letters

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Retrotransposons, including LINE-1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy-paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double-strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi-layered regulatory processes to prevent the dangerous effects of their expression. In recent years, significant progress was made in revealing how retrotransposon biology intertwines with general posttranscriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post-transcriptional factors in the biology of retrotransposons, focusing on LINE-1. I emphasize general RNA metabolisms such as methylation of adenine (m 6 A), RNA 3 0 -end polyadenylation and uridylation, RNA decay and translation regulation. I discuss the effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles.

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

Cited by 54 publications

References 101 publications

The homeobox transcription factor DUXBL controls exit from totipotency

The homeobox transcription factor DUXBL controls exit from totipotency

Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases

An update on post‐transcriptional regulation of retrotransposons

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