Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE261614 | GEO | 2025/01/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

MERVL/Zscan4 network activation results in transient genome-wide DNA demethylation of mESCs

Project description:MERVL/Zscan4 network activation results in transient genome-wide DNA demethylation of mESCs

| PRJEB15553 | ENA

MERVL/Zscan4 network activation results in transient genome-wide DNA demethylation of mESCs

Project description:Several previous studies have noted a rare sub-population of murine Embryonic Stem Cells (mESCs) which seem to express genes otherwise specific to the 2-cell stage of embryonic development. Here we sorted single cells from a MERVL/Zscan4 reporter line to investigate the continuum of expression as cells go from the standard state to this 2C-like state.

2016-09-30 | E-MTAB-5058 | biostudies-arrayexpress

IGR_DNA_DAMAGE_STUDY_FM

Project description:Granzyme B plays a key role in cell-mediated programmed cell death. We previously demonstrated that p53 is a functional determinant in the Granzyme B-induced cytotoxic T lymphocyte response. However, the pathways leading to activation of p53 by Granzyme B remain incompletely understood. We now demonstrate that Granzyme B induced DNA damage signaling as revealed by histone H2AX phosphorylation and subsequent activation of the stress kinase CHK2. Confocal microscopy analysis indicates that Granzyme B treatment of tumor cells induced an early translocation of endonuclease caspase-activated DNase. DNA microarray based global transcriptional profiling and RT-PCR indeed revealed genes related to DNA damage. Among these genes, hSMG-1, a genotoxic stress-activated protein, was constantly upregulated in tumor cells following Granzyme B treatment. Knockdown of the hSMG-1 gene in T1 tumor target cell line resulted in a significant inhibition of Granzyme B- and CTL-induced killing. Our data suggest that Granzyme B may exert cell death through DNA damage signaling and uncover a novel molecular link between the DNA damage pathway and Granzyme B-induced cell death.

2012-02-15 | E-TABM-1116 | biostudies-arrayexpress

Mus musculus

Project description:MERVL/Zscan4 network activation results in transient genome-wide DNA demethylation of mESCs

| PRJNA339313 | 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

p53 binding in mouse embryonic stem cells untreated or treated with adriamycin

Project description:Both p53 and the Wnt signaling pathways play important roles in tumorigenesis and development. However, few studies, particularly on a genome-wide scale, have linked these two pathways. Here we show that p53 directly regulates the Wnt signaling pathway in murine embryonic stem cells (mESCs) using an integrated genome-wide approach. A chromatin-immunoprecipitation-based microarray assay (ChIP-chip) reveals that the Wnt signaling pathway is significantly over-represented in p53 bound genes. Using gene expression microarray and real-time PCR, we demonstrate that the expressions of many Wnts are robustly induced by various stresses, including DNA damage and hypoxia that activate p53. Importantly, the activation of p53 is a prerequisite for the induction of Wnts. Moreover, conditional medium (CM) collected from ultraviolet (UV)-treated mESCs contains an anti-differentiation activity, which can be lowered by either the addition of Wnt signaling inhibitors into the CM or the reduction of p53 levels in UV-treated mESCs. These results suggest that stressed mESCs utilize the p53-Wnt signaling axis to signal neighboring mESCs to delay the differentiation. Together, our results uncover a novel connection between p53 and the Wnt signaling pathways in mediating cell-to-cell communication in mESCs, and provide insights into the functions of these two pathways in tumorigenesis and development

2010-01-19 | GSE16427 | GEO

Iwamoto2010 - Cell cycle reponse to DNA damage

Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.

2024-09-02 | BIOMD0000000939 | BioModels

p53 regulates the Wnt signaling pathway in murine embryonic stem cells

Project description:Genome-wide analysis of gene expression changes in murine embryonic stem cells (R1E cells) treated with Ultraviolet and adriamycin Both p53 and the Wnt signaling pathways play important roles in tumorigenesis and development. However, few studies, particularly on a genome-wide scale, have linked these two pathways. Here we show that p53 directly regulates the Wnt signaling pathway in murine embryonic stem cells (mESCs) using an integrated genome-wide approach. A chromatin-immunoprecipitation-based microarray assay (ChIP-chip) reveals that the Wnt signaling pathway is significantly over-represented in p53 bound genes. Using gene expression microarray and real-time PCR, we demonstrate that the expressions of many Wnts are robustly induced by various stresses, including DNA damage and hypoxia that activate p53. Importantly, the activation of p53 is a prerequisite for the induction of Wnts. Moreover, conditional medium (CM) collected from ultraviolet (UV)-treated mESCs contains an anti-differentiation activity, which can be lowered by either the addition of Wnt signaling inhibitors into the CM or the reduction of p53 levels in UV-treated mESCs. These results suggest that stressed mESCs utilize the p53-Wnt signaling axis to signal neighboring mESCs to delay the differentiation. Together, our results uncover a novel connection between p53 and the Wnt signaling pathways in mediating cell-to-cell communication in mESCs, and provide insights into the functions of these two pathways in tumorigenesis and development.

2010-01-19 | GSE16428 | GEO

DUX-miR-344-ZMYM2-mediated activation of MERVL LTRs induces a totipotent 2C-like state [RNA-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 | GSE119819 | GEO

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

2020-02-06 | GSE119817 | GEO