Hijacking of transcriptional condensates by endogenous retroviruses

Asimi, Vahid; Kumar, Abhishek Sampath; Niskanen, Henri; Riemenschneider, Christina; Hetzel, Sara; Naderi, Julian; Fasching, Nina; Popitsch, Niko; Du, Manyu; Kretzmer, Helene; Smith, Zachary D.; Weigert, Raha; Walther, Maria; Mamde, Sainath; Meierhofer, David; Wittler, Lars; Buschow, René; Timmermann, Bernd; Cissé, Ibrahima; Ameres, Stefan L.; Meissner, Alexander; Hnisz, Denes

doi:10.1038/s41588-022-01132-w

Cited by 44 publications

(40 citation statements)

References 80 publications

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“…Our data show that DUX-induced chromatin opening and MERVL activation leads to the formation of DUX-associated nuclear foci and the recruitment of the TRIM24/33/DUXBL complex. Indeed, ERV derepression in ESC leads to the formation of transcriptional condensates associated with transcribing ERV loci 48 . At these foci, TRIM24/33 further recruit HDAC proteins and HP1 promoting heterochromatin formation.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

The homeobox transcription factor DUXBL controls exit from totipotency

Vega-Sendino

Olbrich

Stein

et al. 2022

Preprint

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“…Protein expression of mCherry constructs was performed as previously described 6 , 33 , but with modifications to mCherry–MED1-IDR expression, which was performed in the presence of 400 μg ml –1 kanamycin. Protein expression of meGFP–HMGB1 constructs was performed in Rosetta (DE3)pLysS cells (Sigma-Aldrich) in the presence of 25 µg ml –1 chloramphenicol and 100 μg ml –1 ampicillin.…”

Section: Methodsmentioning

confidence: 99%

“…We therefore tested whether the frameshift mutation alters the partitioning of HMGB1 into nuclear condensates. Using purified marker proteins, we assembled the following model condensates: recombinant mCherry-tagged MED1 IDR droplets as an in vitro model for Mediator co-activator condensates 29 , 31 , 33 ; mCherry-tagged HP1α droplets as an in vitro model for heterochromatin 34 ; and mCherry-tagged NPM1 droplets as an in vitro model for the granular component of the nucleolus 35 . Wild-type and mutant HMGB1 proteins were then added to the droplets (Fig.…”

Section: Altered Hmgb1 Phase Separation In Vitromentioning

confidence: 99%

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Mensah

Niskanen

Magalhães

et al. 2023

Nature

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Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1–3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6–8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

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“…RNA molecules are pervasive components of active transcriptional regulatory loci (Asimi et al, 2022;Henninger et al, 2021;Kaikkonen and Adelman, 2018;Seila et al, 2008;Sharp et al, 2022) and have been implicated in the formation and regulation of spatial compartments (Quinodoz et al, 2021). The noncoding RNAs produced from enhancers and promoters are known to affect gene expression (Kaikkonen and Adelman, 2018), and plausible mechanisms by which these RNA species could influence gene regulation have been proposed to include binding to cofactors and chromatin regulators (Bose et al, 2017;Lai et al, 2013;Long et al, 2017), and electrostatic regulation of condensate compartments (Henninger et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Transcription factors interact with RNA to regulate genes

Oksuz

Henninger

Warneford-Thomson

et al. 2022

Preprint

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Transcription factors (TFs) orchestrate the gene expression programs that define each cell's identity. The canonical TF accomplishes this with two domains, one that binds specific DNA sequences and the other that binds protein coactivators or corepressors. We find that at least half of TFs also bind RNA, doing so through a previously unrecognized domain with sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat. RNA-binding contributes to TF function by promoting the dynamic association between DNA, RNA and TF on chromatin. TF-RNA interactions are a conserved feature essential for vertebrate development and disrupted in disease. We propose that the ability to bind DNA, RNA and protein is a general property of many TFs and is fundamental to their gene regulatory function.

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Hijacking of transcriptional condensates by endogenous retroviruses

Cited by 44 publications

References 80 publications

The homeobox transcription factor DUXBL controls exit from totipotency

The homeobox transcription factor DUXBL controls exit from totipotency

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Transcription factors interact with RNA to regulate genes

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