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Increased DNA replication length offsets developmental defects induced by hypomorphic DNA methylcytosine methyltransferase activity [RNA-Seq]

ABSTRACT: Dnmt1 is a key methyltransferase involved in the maintenance of DNA methylation. To determine whether developmental defects induced by hypomorphic DNA 5-methylcytosine methyltransferase activity can be offset by increasing DNA replication time, we produced fish that were mutant for both dnmt1 and DNA polymerase epsilon (pole1) and compared their whole genome bisultite sequencing and gene expression profiles to WT ones. We further determine that the observed rescue effect by pole1 is specific to dnmt1 by comparing whole-genome bisulfite sequencing and gene expression profiles of mutants for the Methionine Adenosyltransferase 2A (mat2aa) and microchromosome 10 (mcm10)

ORGANISM(S): Danio rerio

PROVIDER: GSE181571 | GEO | 2023/11/24

REPOSITORIES: GEO

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Increased DNA replication length offsets developmental defects induced by hypomorphic DNA methylcytosine methyltransferase activity [Bisulfite-Seq]

Project description:Dnmt1 is a key methyltransferase involved in the maintenance of DNA methylation. To determine whether developmental defects induced by hypomorphic DNA 5-methylcytosine methyltransferase activity can be offset by increasing DNA replication time, we produced fish that were mutant for both dnmt1 and DNA polymerase epsilon (pole1) and compared their whole genome bisultite sequencing and gene expression profiles to WT ones. We further determine that the observed rescue effect by pole1 is specific to dnmt1 by comparing whole-genome bisulfite sequencing and gene expression profiles of mutants for the Methionine Adenosyltransferase 2A (mat2aa) and microchromosome 10 (mcm10)

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Increased DNA replication length offsets developmental defects induced by hypomorphic DNA methylcytosine methyltransferase activity

Project description:Increased DNA replication length offsets developmental defects induced by hypomorphic DNA methylcytosine methyltransferase activity

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Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dys-regulation of Epithelial-Mesenchymal Transition and subcellular re-localization of Beta-Catenin

Project description:DNA methyltransferase I plays the central role in maintenance of CpG DNA methylation patterns across the genome and alteration of CpG methylation patterns is a frequent and significant occurrence across many cancers. Cancer cells carrying hypomorphic alleles of Dnmt1 have become important tools for understanding Dnmt1 function and CpG methylation. In this study, we analyse colorectal cancer cells with a homozygous deletion of exons 3 to 5 of Dnmt1, resulting in reduced Dnmt1 activity. Although this cell model has been widely used to study the epigenome, the effects of the Dnmt1 hypomorph on cell signalling pathways and the wider proteome are largely unknown. In this study, we perform the first quantitative proteomic analysis of this important cell model and identify multiple signalling pathways and processes that are significantly dysregulated in the hypomorph cells. In Dnmt1 hypomorph cells, we observed a clear and unexpected signature of increased Epithelial-to-Mesenchymal transition (EMT) markers as well as reduced expression and sub-cellular re-localization of Beta-Catenin. Expression of wild-type Dnmt1 in hypomorph cells or knock-down of wild-type Dnmt1 did not recapitulate or rescue the observed protein profiles in Dnmt1 hypomorph cells suggesting that hypomorphic Dnmt1 causes changes not solely attributable to Dnmt1 protein levels. In summary we present the first comprehensive proteomic analysis of the widely studied Dnmt1 hypomorph colorectal cancer cells and identify redistribution of Dnmt1 and its interaction partner Beta-Catenin

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Increased DNA replication length offsets developmental defects induced by hypomorphic DNA methylcytosine methyltransferase activity [Bisulfite-Seq]

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Increased DNA replication length offsets developmental defects induced by hypomorphic DNA methylcytosine methyltransferase activity [RNA-Seq]

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S-adenosylhomocysteine hydrolase participates in DNA methylation inheritance

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Protracted NP95 binding to hemimethylated DNA disrupts SETDB1-mediated proviral silencing [RNA-seq]

Project description:Genetic ablation of the maintenance methyltransferase Dnmt1 induces widespread demethylation and transcriptional activation of CpG-rich IAP (intracisternal A particle) proviruses. Here, we report that this phenomenon is not simply a consequence of loss of DNA methylation. By exploiting conditional deletions of Dnmt1 and Np95, each of which is essential for maintenance methylation, we find that while IAPs are indeed de-repressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these proviruses remain silenced in Np95-ablated cells, despite similar kinetics of passive demethylation. Paradoxically, transient IAP activation in Dnmt1-ablated ESCs requires the presence of NP95. We subsequently show that in the absence of NP95, the H3K9 methyltransferase SETDB1 maintains IAP silencing; while in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA perturbs SETDB1-dependent H3K9me3 deposition. Taken together, these observations reveal that following acute loss of Dnmt1, H3K9 methylation-dependent IAP silencing is disrupted by aberrant NP95 binding to hemimethylated DNA. RNA-seq for Np95, Dnmt1 and Setdb1 wt, single conditional KO (cKO) and double cKO ES cells; RRBS-seq for Dnmt1 and Np95 single and double cKO ESCs; Myc-tagged NP95, DNMT1 ChIP-seq; and wt and Np95wt and cKO H3K9me3 ChIP-seq.

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Histone ubiquitination-methylation crosstalk involving UHRF1 and SUV39H1/2 reinforces heterochromatin states in response to DNA hypomethylation

Project description:Histone H3 mono-ubiquitination, catalyzed by the RING E3 ubiquitin ligase UHRF1, is appreciated as a docking site for DNMT1 during DNA replication to facilitate DNA methylation maintenance. Its functions beyond this are unknown. Here, we identify simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/2-dependent H3K9me3 as prominent epigenetic alterations accompanying DNA hypomethylation induced by DNMT1 inhibition. Integrative epigenomics analyses reveal that transient accumulation of hemi-methylated DNA, resulting from incomplete DNA methylation maintenance, stimulates UHRF1-dependent H3K18ub at CpG islands that nucleates new domains of H3K9me3 and impedes PRC2 activity in these genomic regions. Notably, H3K18ub enhances the methyltransferase activity of SUV39H1/2, leading to increased H3K9me3 at these CpG island promoters. Blocking H3K18ub-dependent SUV39H1/2 activity enhances the efficacy of DNMT1 inhibitors. Collectively, these findings reveal a novel histone ubiquitination-methylation crosstalk mechanism that reinforces heterochromatin states in the absence of DNA methylation and proposes new strategies for improving cancer epigenetic therapy.

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Protracted NP95 binding to hemimethylated DNA disrupts SETDB1-mediated proviral silencing [RNA-seq]

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