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Targets and genomic constraints of ectopic Dnmt3b expression

ABSTRACT: Targets and genomic constraints of ectopic Dnmt3b expression

PROVIDER: PRJNA483553 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7627180.fastq.gz	Fastqsanger.gz
	SRR7627190.fastq.gz	Fastqsanger.gz
	SRR7627200.fastq.gz	Fastqsanger.gz
	SRR7627210.fastq.gz	Fastqsanger.gz
	SRR7627220.fastq.gz	Fastqsanger.gz

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Targets and genomic constraints of ectopic Dnmt3b expression

Project description:DNA methylation plays an essential role in mammalian genomes, hence DNA methyltransferase expression is tightly controlled. Deregulation of the de novo enzyme DNMT3B is frequently observed in many diseases, yet little is known about its ectopic genomic targets. Here we used an inducible transgenic mouse model to identify rules delineating abnormal DNMT3B targeting and explore the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpGs to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually antagonistic at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation and its depletion has minimal affect on ectopic methylation targets or levels in mouse embryonic fibroblasts. Our multilayered genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a hit-and-run model that induces hypermethylation and provides insights for interpreting the cancer methylome.

2018-11-20 | GSE117909 | GEO

Targets and genomic constraints of ectopic Dnmt3b expression.

Project description:DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.

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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis

Project description:Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis

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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (RRBS)

Project description:The de novo DNA methyltransferases Dnmt3a and Dnmt3b are of crucial importance in hematopoietic stem cells, and Dnmt3b has recently been shown to play a role in genic methylation. Forced Dnmt3b expression induced widespread DNA hypermethylation in myc-bcl2 induced leukemias, especially at promoters and gene bodies of stem cell-related genes. MLL-AF9 induced leukemogenesis showed much less pronounced DNA hypermethylation upon Dnmt3b expression. Nonetheless, leukemogenesis was delayed in both models with a shared core set of DNA hypermethylated regions and suppression of stem cell-related genes. Our findings indicate a critical role for Dnmt3b-mediated DNA methylation in leukemia development and maintenance of LSC function. To investigate how Dnmt3b-mediated DNA methylation affects leukemogenesis, we analyzed leukemia development under conditions of high and physiological methylation levels in a tetracycline-inducible knockin mouse model. High expression of Dnmt3b slowed leukemia development in serial transplantations and impaired leukemia stem cell (LSC) function.

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Project description:Dnmt3b is a DNA methyltransferase, an enzyme which methylates genomic DNA, contributes to genomic stability and transcriptional regulation. Inactivation of Dnmt3b in mice results in embryonic lethality at E13.5. It is however unclear which activities are responsible for this phenomenon. Here, we analyzed methylation and gene expression in Dnmt3b+/+ (WT), Dnmt3b-/- (3bKO) and Dnmt3bCI/CI (3bKI) embryos at E11.5.

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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (expression)

Project description:Here, we analyzed global gene expression changes that were associated with over expression of Dnmt3b in MLL-AF9 induced leukemias using the Affymetrix microarray platform. Changes in global gene expression were determined with Affymetrix microarrays in MLL-AF9 induced leukemias over expressing Dnmt3b.

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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (RRBS)

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Expression data from normal thymocytes, 24 day pre-tumor Dnmt3b-deficient thymocytes, Wild-Type Tumors, and Dnmt3b-deficient Tumors

Project description:Dnmt3b is a DNA methytransferase which is an enzyme that methylated genomic DNA which contributes to genomic stability and transcriptional regulation. We genetically inactivated Dnmt3b in the hematopoeitic compartment in the context of MYC overexpression and analysed the resulting thymic lymphomas.

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