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A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells [E14TG2a]

ABSTRACT: A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells [E14TG2a]

PROVIDER: PRJNA1243304 | ENA |

REPOSITORIES: ENA

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A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells [E14TG2a]

Project description:The murine endogenous retrovirus MERVL is closely associated with the developmental potential of totipotency, manifesting dynamic and reversible activation within a small population of in vitro-cultured mouse embryonic stem cells (mESCs). While numerous regulators have been identified to influence the on and off switches of MERVL, how its activation is linked to the cellular decision-making of mESCs remains poorly understood. In this study, our genome-wide knockout screen uncovered an intimate relationship between MERVL activation and DNA damage response pathways. Specifically, we found that deficiency of Ints7, a backbone subunit of the Integrator complex, resulted in increased DNA damage, stabilization of p53, and hence transcriptional activation of MERVL. Moreover, we revealed that MERVL activation upon Ints7 knockdown was frequently accompanied by the activation of caspase 3. Intriguingly, a proportion of the caspase-activated mESCs were able to switch on MERVL meanwhile circumvent apoptosis and evade cell death, resembling a process known as anastasis. Altogether, our study highlights an association between MERVL activation and the p53-dependent cell fate plasticity in response to DNA damage, suggesting that limited caspase activation can alter developmental potential of stem cells.

2025-07-29 | GSE293177 | GEO

A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells

2025-01-01 | GSE261614 | GEO

A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells [CUT&Tag]

2025-07-01 | GSE300876 | GEO

A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells

Project description:A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells

| PRJNA1088116 | ENA

A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells [CUT&Tag]

Project description:A genome-wide screen reveals Ints7 deficiency activates endogenous retrovirus MERVL, accompanied by anastasis of embryonic stem cells [CUT&Tag]

| PRJNA1282576 | ENA

Murine Endogenous Retrovirus MERVL is essential for the transition from Totipotency to Pluripotency during Preimplantation Development

Project description:Zygotic genome activation (ZGA) is a critical post-fertilization step that promotes totipotency and allows different cell fates to emerge in the developing embryo. MERVL, murine endogenous retrovirus-L, is transiently upregulated at the 2-cell stage around the time of ZGA. Although MERVL expression is widely used as a marker of totipotency, the role of this retrotransposon in mouse embryogenesis remains elusive. Here, we develop methods for consistent knockdown (KD) and inactivation of interspersed copies of MERVL and show that MERVL transcripts, but not encoded retroviral proteins and their long terminal repeat (LTR) promoter that drives chimeric transcripts with host genes, is essential for accurate regulation of the host transcriptome and chromatin state during preimplantation development. Both KD and CRISPRi-based repression of MERVL result in embryonic lethality due to defects in differentiation and genomic stability. Furthermore, transcriptome and epigenome analysis revealed that loss of MERVL transcript led to retain an accessible chromatin state at, and aberrant expression of, a subset of 2-cell specific genes at mid-preimplantation stages. Taken together, our results suggest a model in which an endogenous retrovirus plays a critical role in regulating host cell fate potential.

2023-02-12 | GSE196520 | GEO

Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes.

Project description:Endogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.

| S-EPMC7145578 | biostudies-literature

Dot1l cooperates with Npm1 to repress endogenous retrovirus MERVL in embryonic stem cells

Project description:Dot1l is a histone methyltransferase without a SET domain and is responsible for H3K79 methylation, which marks active transcription. In contradiction, Dot1l also participates in silencing gene expression. The target regions and mechanism of Dot1l in repressing transcription remain enigmatic. Here, we examined the possibility for Dot1l as an repressor of MERVL, which is a marker of 2-cell-like cells. Mechanistically, Dot1l interacted with and colocalized with Npm1 on MERVL, and depletion of Npm1 similarly augmented MERVL expression.

2023-07-17 | GSE201849 | GEO

Dot1l cooperates with Npm1 to repress endogenous retrovirus MERVL in embryonic stem cells

Project description:Dot1l cooperates with Npm1 to repress endogenous retrovirus MERVL in embryonic stem cells

| PRJNA833294 | ENA

DUX-miR-344-ZMYM2-mediated activation of MERVL LTRs induces a totipotent 2C-like state [ATAC-seq]

Project description:Mouse embryonic stem cells (ESCs) sporadically express preimplantation two-cell-stage (2C) transcripts, including MERVL endogenous retrovirus and Zscan4 cluster genes. Such 2C-like cells (2CLCs) can contribute to both embryonic and extraembryonic tissues when reintroduced into early embryos. We examined global nucleosome occupancy and gene expression in 2CLCs and identified miR-344 as the noncoding molecule that positively controls 2CLC potency. We found that activation of endogenous MERVL or miR-344-2 alone is sufficient to induce 2CLCs with induction of 2C genes and an expanded potency. Mechanistically, miR-344 is activated by the 2C-state driver DUX and post-transcriptionally represses ZMYM2 and LSD1, which recruit the HDAC corepressor to MERVL LTR for transcriptional repression. Consistently, zygotic depletion of Zmym2 compromises the totipotency-to-pluripotency transition during early development. Our studies establish the novel DUX->miR-344--|Zmym2/Lsd1 axis that controls MERVL for expanded stem cell potency.

2020-02-06 | GSE119817 | GEO

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