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Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome

ABSTRACT: Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome

PROVIDER: PRJNA831845 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18914402_1.fastq.gz	Fastqsanger.gz
	SRR18914403_1.fastq.gz	Fastqsanger.gz
	SRR18914404_1.fastq.gz	Fastqsanger.gz
	SRR18914405_1.fastq.gz	Fastqsanger.gz
	SRR18914406_1.fastq.gz	Fastqsanger.gz

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Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome

Project description:The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on DNMT1. Functional studies further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that is preferentially at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

2023-07-26 | PXD043031 | Pride

Inhibition of DNMT1 methyltransferase activity via glucose-regulated <i>O</i>-GlcNAcylation alters the epigenome.

Project description:The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

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Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome

Project description:Profiling of DNA methylation

2023-07-22 | GSE201470 | GEO

DNMT1

Project description:Monodelphis domestica DNMT1, Monodelphis domestica DNA (cytosine-5-)-methyltransferase 1 (DNMT1), mRNA. [Source:RefSeq mRNA;Acc:NM_001032969], is expressed in 1 baseline experiment(s);

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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

2021-09-08 | PXD014632 | Pride

Dnmt1

Project description:Rattus norvegicus Dnmt1, DNA methyltransferase 1 [Source:RGD Symbol;Acc:620979], is differentially expressed in 21 experiment(s);

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Dnmt1

Project description:Rattus norvegicus Dnmt1, DNA methyltransferase 1 [Source:RGD Symbol;Acc:620979], is expressed in 5 baseline experiment(s);

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GlcNAcylation of histone H2B facilitates its monoubiquitination

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DNMT1

Project description:Homo sapiens DNMT1, DNA methyltransferase 1 [Source:HGNC Symbol;Acc:HGNC:2976], is differentially expressed in 206 experiment(s);

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Project description:Equus caballus DNMT1, DNA methyltransferase 1 [Source:VGNC Symbol;Acc:VGNC:17255], is expressed in 1 baseline experiment(s);

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