Conservation and innovation in the DUX4-family gene network

Whiddon, Jennifer L.; Langford, Ashlee T; Wong, Chao-Jen; Zhong, Jun; Tapscott, Stephen J.

doi:10.1038/ng.3846

Cited by 298 publications

(350 citation statements)

References 37 publications

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“…These findings overall indicate that ATR-activated ESCs gain expanded developmental potential in vitro and in vivo, and that this effect is mediated by DUX, whose physiological role in the activation of cleavage-stage transcription program has been reported in previous works [9][10][11] .…”

Section: Atr-activated Escs Gain Expanded Developmental Potentialsupporting

confidence: 78%

“…Candidate-based screening identifies the involvement of the GRSF1 in the post-transcriptional regulation of the Dux mRNA downstream of ATR Next, to identify the mediating factors regulating Dux expression in response to ATR activation, we performed a siRNA-based RT-qPCR screening using a library targeting 148 genes ( Fig. 5a) and quantified the expression level of Zscan4, a bona fide DUX downstream target, as the final readout [9][10][11] .…”

Section: Etaa1-mediated Activation Of Atr Elevates the Number Of 2c-lmentioning

confidence: 99%

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ATR expands embryonic stem cell fate potential in response to replication stress

Atashpaz

Shams

González

et al. 2020

Preprint

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Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood.Here, we uncovered an ATR-and CHK1-mediated transcriptional response to replication stress (RS) in ESCs that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GSRF1 dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extraembryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS. BackgroundESCs are characterized by self-renewal and the ability to propagate for several cycles in vitro and in vivo 1 . Even if ESCs exhibit several markers of RS 2 , they are able to maintain genome integrity more efficiently than differentiated cells 1 . The mechanisms underlying such distinctive feature are largely unknown. ESC colonies harbor a small transient subpopulation of cells (2C-like cells) with functional andtranscriptional features of totipotent 2C-stage embryos 3-5 . Transition to 2C-like cells has been shown to promote maintenance of genome integrity and survival of ESCs in long-term culture 6-8 . In addition, several studies have demonstrated that transition to the 2C-like state confers expanded developmental potential to ESCs, making them capable of contributing to both embryonic and extra-embryonic tissues (also referred to as bidirectional cell fate potential) 3-5 . However, the molecular players underlying the transition to the 2C-like state in ESC culture and its possible physiological relevance in vivo in maintaining genome integrity and expanding cell fate potential in a developing embryo are not fully understood.Here we provide several lines of evidence that ATR and CHK1-mediated response to RS triggers the activation of 2C-specific genes in ESCs and mouse embryos. This transition is hampered in ESCs derived from ATR-deficient Seckel and CHK1 haploinsufficient mouse models and following ATR or CHK1 inhibition. Significantly, we show that ETAA1-mediated ATR activation is sufficient to trigger the formation of 2C-like cells in the absence of RS.Mechanistically, ATR-induced transition to 2C-like state is mediated by post-transcriptional regulation of the Dux gene, which shapes the transcriptional signature of 2C-like cells and totipotent 2C-stage embryos in placental mammals 9-11 . ATR-dependent regulation of Du...

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Section: Atr-activated Escs Gain Expanded Developmental Potentialsupporting

confidence: 78%

Section: Etaa1-mediated Activation Of Atr Elevates the Number Of 2c-lmentioning

confidence: 99%

ATR expands embryonic stem cell fate potential in response to replication stress

Atashpaz

Shams

González

et al. 2020

Preprint

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“…These results confirm that Arg145 in HD2, in place of Glu70 in HD1, is important for the unique preference of HD2 for 5′-T G AT-3′. Mouse Dux (mDux), which has RRNR and RRAR at this position in HD1 and HD2, respectively (Figure 2D), was reported to have the canonical target sequence of 5′- T G AT TCA AT C A -3′ (Eidahl et al, 2016; Whiddon et al, 2017). Consistent with the above results, HD1-RRAR, HD2HD2, and mDux constructs all showed strong preference for the canonical mDux target sequence (Figure 2C).…”

Section: Resultssupporting

confidence: 63%

Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA

et al. 2018

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SUMMARY Double homeobox (DUX) transcription factors are unique to eutherian mammals. DUX4 regulates expression of repetitive elements during early embryogenesis, but misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and translocations overexpressing the DUX4 double homeodomain cause B cell leukemia. Here, we report the crystal structure of the tandem homeodo-mains of DUX4 bound to DNA. The homeodomains bind DNA in a head-to-head fashion, with the linker making anchoring DNA minor-groove interactions and unique protein contacts. Remarkably, despite being tandem duplicates, the DUX4 homeodomains recognize different core sequences. This results from an arginine-to-glutamate mutation, unique to primates, causing alternative positioning of a key arginine side chain in the recognition helix. Mutational studies demonstrate that this primate-specific change is responsible for the divergence in sequence recognition that likely drove coevolution of embryonically regulated repeats in primates. Our work provides a framework for understanding the endogenous function of DUX4 and its role in FSHD and cancer.

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“…Maternal deletion of Yap1 results in failure to form a blastocyst, downregulation of ~3000 ZGA transcripts, and upregulation of ~1300 otherwise degraded transcripts. Other activators include the Zscan transcription factors, which are expressed specifically in the 2 cell embryo (Falco et al, 2007; Ko, 2016), NFYa, which likely directly regulates some genes activated in the 2-cell embryo (Lu et al, 2016), and the DUX (mouse) and DUX4 (human) homeobox transcription factors (De Iaco et al, 2017; Hendrickson et al, 2017; Whiddon et al, 2017). Intriguingly, DUX4 directly induces several hundred early human ZGA target genes, including HERVL retrotransposons, at the 4–8 cell stage.…”

Section: Transcriptional Activation By Activatorsmentioning

confidence: 99%

“…Intriguingly, DUX4 directly induces several hundred early human ZGA target genes, including HERVL retrotransposons, at the 4–8 cell stage. DUX4/DUX family genes are found in telomeric and pericentromeric regions as multicopy loci and appear specific to placental mammals, suggesting that DUX transcription factors could be critical drivers of embryonic genome activation in the mammalian lineage (De Iaco et al, 2017; Hendrickson et al, 2017; Whiddon et al, 2017). DUX itself is zygotically expressed by unknown mechanisms, indicating that key maternally deposited regulators of human and mouse ZGA remain to be identified.…”

Section: Transcriptional Activation By Activatorsmentioning

confidence: 99%

Zygotic Genome Activation in Vertebrates

2017

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The first major developmental transition in vertebrate embryos is the maternal-to-zygotic transition (MZT) when maternal mRNAs are degraded and zygotic transcription begins. During the MZT, the embryo takes charge of gene expression to control cell differentiation and further development. This spectacular organismal transition requires nuclear reprogramming and the initiation of RNAPII at thousands of promoters. Zygotic genome activation (ZGA) is mechanistically coordinated with other embryonic events including changes in the cell cycle, chromatin state, and nuclear-to-cytoplasmic component ratios. Here, we review progress in understanding vertebrate ZGA dynamics in frogs, fish, mice, and humans to explore differences and emphasize common features.

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Conservation and innovation in the DUX4-family gene network

Cited by 298 publications

References 37 publications

ATR expands embryonic stem cell fate potential in response to replication stress

ATR expands embryonic stem cell fate potential in response to replication stress

Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA

Zygotic Genome Activation in Vertebrates

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