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DUX4, a Zygotic Genome Activator, Is Involved in Oncogenesis and Genetic Diseases Anna Karpukhina, Yegor Vassetzky

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DUX4, a Zygotic Genome Activator, Is Involved in Oncogenesis and Genetic Diseases Anna Karpukhina, Yegor Vassetzky DUX4, a Zygotic Genome Activator, Is Involved in Oncogenesis and Genetic Diseases Anna Karpukhina, Yegor Vassetzky To cite this version: Anna Karpukhina, Yegor Vassetzky. DUX4, a Zygotic Genome Activator, Is Involved in Onco- genesis and Genetic Diseases. Ontogenez / Russian Journal of Developmental Biology, MAIK Nauka/Interperiodica, 2020, 51 (3), pp.176-182. 10.1134/S1062360420030078. hal-02988675 HAL Id: hal-02988675 https://hal.archives-ouvertes.fr/hal-02988675 Submitted on 17 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ISSN 1062-3604, Russian Journal of Developmental Biology, 2020, Vol. 51, No. 3, pp. 176–182. © Pleiades Publishing, Inc., 2020. Published in Russian in Ontogenez, 2020, Vol. 51, No. 3, pp. 210–217. REVIEWS DUX4, a Zygotic Genome Activator, Is Involved in Oncogenesis and Genetic Diseases Anna Karpukhinaa, b, c, d and Yegor Vassetzkya, b, * aCNRS UMR9018, Université Paris-Sud Paris-Saclay, Institut Gustave Roussy, Villejuif, F-94805 France bKoltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, 119334 Russia cBelozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119234 Russia dFaculty of Bioengineering and Bioinformatics, Moscow State University, Moscow, 119234 Russia *e-mail: [email protected] Received February 3, 2020; revised February 12, 2020; accepted February 14, 2020 Abstract—After fertilization, the genome is transcriptionally quiescent to allow zygote reprogramming that relies on the RNA and proteins accumulated in the oocyte and ensures the transition from the differentiated germ cells to a totipotent state. Reprogramming is followed by zygotic genome activation (ZGA). DUX4 gene encoding for a double homeobox transcription factor is one of the key ZGA drivers in humans. Its expression, essential for embryo development, is subject to precise temporal regulation and is normally observed only at early cleavage stages. DUX4 is efficiently silenced in most somatic tissues via numerous epigenetic mecha- nisms, while its aberrant expression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4 expression following chromosomal rearrangements is also observed in a subset of leukemias and sarcomas; it leads to anti-cancer immune activity suppression. Keywords: DUX4, zygotic genome activation (ZGA), oncogenesis, muscular dystrophy DOI: 10.1134/S1062360420030078 INTRODUCTION Joseph et al., 2017). Rapid cell cycles in the early After fertilization, the newly formed genome is embryo of many species leave almost no time for tran- comprised of maternal and paternal genetic material, scription between divisions (Shermoen and O’Farrell, each with its own chromatin organization, and needs 1991; Rothe et al., 1992). As division slows down and to be remodeled to a globally accessible state before it can cell-cycle lengthens, ZGA becomes possible (Kimel- be transcribed. Zygote reprogramming occurs immedi- man et al., 1987). ZGA is also associated with chroma- ately after fertilization while the fertilized oocyte is tran- tin remodelling. Finally, essential transcription factors scriptionally quiescent (Newport and Kirschner, 1982; inherited in the form of maternal mRNA need time to Tadros and Lipshitz, 2009). This reprogramming relies be polyadenylated, translated and accumulated at cer- on RNAs and proteins accumulated in the oocyte tain levels to activate transcription (Veenstra et al., before fertilization and ensures the transition of the 1999; Guven-Ozkan et al., 2008). Here we will review oocyte and the spermatozoon which have formed the the family of DUX transcription factors that partici- zygote to a totipotent state so that they can give rise to pate in mammalian ZGA (De Iaco et al., 2017). different cell types. The process known as maternal- to-zygotic transition (MZT) (Tadros and Lipshitz, 2009) follows reprogramming. MZT includes zygotic DUX GENE ORIGIN AND EVOLUTION genome activation (ZGA) and gradual degradation of DUX gene family is represented by intronless DUX4 maternal products. After the MZT, the newly formed in primates and Afroteria (elephant, hyrax and tenrec), zygotic genome takes entire control of transcription in Dux in mice and rats, as well as intron-containing the developing embryo. Duxa, Duxb and Duxc in other mammals (Leidenroth The mechanisms driving ZGA are not entirely et al., 2012). One more intron-containing variant, understood; ZGA is at least partially regulated Duxbl (DUXB-like), is found only in mice and rats, through the change in nucleocytoplasmic ratio (New- though its pseudogene forms are also found in pri- port and Kirschner, 1982) which can promote titration mates (Leidenroth and Hewitt, 2010). DUX4 is present of some highly expressed non-specific maternal in the human genome in multiple copies which are repressors, inhibiting transcription from zygotic DNA organized into large (3.3 kb) macrosatellite tandem (Amodeo et al., 2015; Jevtić and Levy, 2015, 2017; repeats (D4Z4 arrays) in the subtelomeric regions of 176 DUX4, A ZYGOTIC GENOME ACTIVATOR 177 chromosome 4q and 10q (Gabriëls et al., 1999). D4Z4 et al., 2017; Hendrickson et al., 2017). DUX4 RNA has is also present elsewhere in the human genome as indi- been detected from the oocyte to four-cell (4C) stage, vidual copies. Similarly, many copies of murine Dux and the transcripts of DUX4 putative targets including are embedded within 4.9 kb repeats (Clapp et al., other ZGA-associated genes such as ZSCAN4, ZFP352 2007). and endogenous retroviral elements (MERVL in mice All DUX proteins possess two DNA-binding and HERVL in humans) are present from two-cell homeodomains (HDs; HD1 and HD2) separated by a (2C) to eight-cell (8C) stages peaking at 8C (De Iaco linker. Though HDs typically bind DNA in dimers, et al., 2017), which corresponds to the major wave of the presence of several HDs within a single protein is ZGA in humans (Vassena et al., 2011). quite unusual and is not observed outside of placental mammals (Eutheria). Duxc, Dux and DUX4 share a Ectopic Dux expression in mouse embryonic stem conserved C-terminal transactivation domain (Leid- cells (mESCs) converts them into two-cell embryo- enroth and Hewitt, 2010; Mitsuhashi et al., 2018). like (‘2C-like’) state. Dux-expressing mESCs reacti- vate expression of “2C” genes and repeat elements, According to the present evolutionary model, the lose the pluripotency associated POU5F1 protein and DUX family appeared following a duplication of a part chromocenters (heterochromatic aggregations) and of a gene containing a single homeobox (Leidenroth acquire chromatin landscape characteristic of the two- and Hewitt, 2010) so that the resulting gene contained cell embryos as determined by ATAC-seq (Hendrick- two tandemly arranged homeoboxes (Lee et al., 2018). son et al., 2017). Alternately, CRISPR/Cas9 knockout The genome of the most recent common ancestor of of Dux in mouse zygotes ex vivo was shown to prevent all placental mammals contained the Duxc double their transition from 2C. KO zygotes did not exhibit homeobox gene, then DUX4 and Dux genes arose via ZGA-specific transcriptional changes and failed to multiple independent retrotransposition events (Leid- form morula/blastocyst (De Iaco et al., 2017). enroth et al., 2012). The two DUX homeodomains belong to the However, more recent studies demonstrate that Paired-homeobox (PAX) branch of homeodomain Dux depletion in vivo is much less harmful and the family, but their similarity to each other is much stron- complete loss of Dux is compatible with mouse devel- ger than to any of the other PAX branch members. opment (Chen and Zhang, 2019; Guo et al., 2019). This supports the hypothesis that the DUX family Homozygous Dux –/– mice survive to adulthood, most probably radiated out following a duplication in albeit they display a slightly reduced frequency than the progenitor of eutherian mammals (Leidenroth expected from the Mendelian distribution and et al., 2012; Lee et al., 2018). A single-homeobox gene reduced developmental potential. RNA-seq profiles of (sDUX) identified in non-mammalian genomes is Dux knockout mouse embryos at late 1C and 2C stages likely to be a homologue of the mammalian DUX do not differ significantly from those of WT (Chen and ancestor (Leidenroth and Hewitt, 2010). Zhang, 2019). Single-cell RNA-seq of 2C embryos at DUX4 is a transcription factor. Its HD domains bind early, middle and late 2C-stages demonstrates that to a specific DNA sequence and this activates gene while a subset of ZGA genes is indeed downregulated expression via the DUX4 transactivation domain. The in Dux KO embryos at the early 2C stage (as compared human DUX4 consensus motif is 5-TAATCTAATCA-3 to WT early 2C), these genes are robustly upregulated (Geng et al., 2012; Yu Zhang et al., 2016). As the two at the late 2C stage (compared to early 2C in Dux KO DUX4 homeodomains are very similar to each other, embryos) indicating that their transcription, though it was first suggested that they bind the two identical delayed, is activated even
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