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Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE267053 | GEO | 2025/02/10

REPOSITORIES: GEO

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Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [ChIP-seq]

Project description:Epigenetic mechanisms are crucial for developmental programming and can be disrupted by environmental stressors, increasing susceptibility to disease. This has sparked interest in therapies for restoring epigenetic balance, but it remains uncertain whether disordered epigenetic mechanisms can be fully corrected. Disruption of DNA methyltransferase 1 (DNMT1), responsible for DNA methylation maintenance, has particularly devastating biological consequences. Therefore, here we explored if rescuing DNMT1 activity is sufficient to reverse the effects of its loss utilizing mouse embryonic stem cells. However, only partial reversal could be achieved. Extensive changes in DNA methylation, histone modifications and gene expression were detected, along with transposable element de-repression and genomic instability. Reduction of cellular size, complexity and proliferation rate were observed, as well as lasting effects in early embryonic lineages and embryoid bodies. Interestingly, by analyzing the impact on imprinted regions, we uncovered 20 regions exhibiting imprinted-like signatures. Notably, while many permanent effects persisted throughout Dnmt1 inactivation and rescue, others arose from the rescue intervention. Lastly, rescuing DNMT1 after differentiation initiation worsened outcomes, reinforcing the need for early intervention. Our findings highlight the far-reaching functions of DNMT1 and provide valuable perspectives on the repercussions of epigenetic perturbations during early development and the challenges of rescue interventions.

2025-02-10 | GSE266929 | GEO

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [mRNA-seq]

Project description:Epigenetic mechanisms are crucial for developmental programming and can be disrupted by environmental stressors, increasing susceptibility to disease. This has sparked interest in therapies for restoring epigenetic balance, but it remains uncertain whether disordered epigenetic mechanisms can be fully corrected. Disruption of DNA methyltransferase 1 (DNMT1), responsible for DNA methylation maintenance, has particularly devastating biological consequences. Therefore, here we explored if rescuing DNMT1 activity is sufficient to reverse the effects of its loss utilizing mouse embryonic stem cells. However, only partial reversal could be achieved. Extensive changes in DNA methylation, histone modifications and gene expression were detected, along with transposable element de-repression and genomic instability. Reduction of cellular size, complexity and proliferation rate were observed, as well as lasting effects in germ layer lineages and embryoid bodies. Interestingly, by analyzing the impact on imprinted regions, we uncovered 20 regions exhibiting imprinted-like signatures. Notably, while many permanent effects persisted throughout Dnmt1 inactivation and rescue, others arose from the rescue intervention. Lastly, rescuing DNMT1 after differentiation initiation worsened outcomes, reinforcing the need for early intervention. Our findings highlight the far-reaching functions of DNMT1 and provide valuable perspectives on the repercussions of epigenetic perturbations during early development and the challenges of rescue interventions.

2025-02-10 | GSE266928 | GEO

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [RNA-seq]

2025-02-10 | GSE266927 | GEO

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [EM-seq]

2025-02-10 | GSE266926 | GEO

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells.

Project description:Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells.

| PRJNA1109408 | ENA

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [mRNA-seq]

Project description:Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [mRNA-seq]

| PRJNA1108729 | ENA

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [RNA-seq]

Project description:Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [RNA-seq]

| PRJNA1108730 | ENA

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [EM-seq]

Project description:Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [EM-seq]

| PRJNA1108731 | ENA

Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [ChIP-seq]

Project description:Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells [ChIP-seq]

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Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality.

Project description:Biallelic expression of Igf2 is frequently seen in cancers because Igf2 functions as a survival factor. In many tumors the activation of Igf2 expression has been correlated with de novo methylation of the imprinted region. We have compared the intrinsic susceptibilities of the imprinted region of Igf2 and H19, other imprinted genes, bulk genomic DNA, and repetitive retroviral sequences to Dnmt1 overexpression. At low Dnmt1 methyltransferase levels repetitive retroviral elements were methylated and silenced. The nonmethylated imprinted region of Igf2 and H19 was resistant to methylation at low Dnmt1 levels but became fully methylated when Dnmt1 was overexpressed from a bacterial artificial chromosome transgene. Methylation caused the activation of the silent Igf2 allele in wild-type and Dnmt1 knockout cells, leading to biallelic Igf2 expression. In contrast, the imprinted genes Igf2r, Peg3, Snrpn, and Grf1 were completely resistant to de novo methylation, even when Dnmt1 was overexpressed. Therefore, the intrinsic difference between the imprinted region of Igf2 and H19 and of other imprinted genes to postzygotic de novo methylation may be the molecular basis for the frequently observed de novo methylation and upregulation of Igf2 in neoplastic cells and tumors. Injection of Dnmt1-overexpressing embryonic stem cells in diploid or tetraploid blastocysts resulted in lethality of the embryo, which resembled embryonic lethality caused by Dnmt1 deficiency.

| S-EPMC133685 | biostudies-literature

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