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Mus musculus

ABSTRACT: DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma

PROVIDER: PRJNA395905 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5870980.fastq.gz	Fastqsanger.gz
	SRR5870979.fastq.gz	Fastqsanger.gz

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DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma

Project description:We performed methylation profiling using RRBS-seq to investigate the role of DNMT3B in MYC-driven tumor maintenance. Comparing tumor cells before and upon DNMT3B knock-down revealed genome-wide changes in the DNA methylation pattern.

2017-07-27 | GSE101907 | GEO

DNMT3B7 disrupts embryonic development and accelerates lymphomagenesis

Project description:Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed transgenic mice expressing DNMT3B7, a common truncated DNMT3B isoform in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Eμ−myc animals. Eμ-myc/DNMT3B7 lymphomas have more chromosomal rearrangements, increased global methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to Eμ-myc lymphomas. Our results demonstrate that a truncated DNMT3B protein can alter tumorigenesis, suggesting a similar role in human tumors. Direct comparison of DNA methylation in lymphoma samples from Eu-Myc vs Eu-Myc/Dnmt3b7 mice.

2010-07-30 | E-GEOD-21273 | biostudies-arrayexpress

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.

2012-02-22 | E-GEOD-30126 | biostudies-arrayexpress

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

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Methylation and gene expression data obtained from Dnmt3b+/+, Dnmt3bD/D and Dnmt3bCI/CI MYC induced T-cell lymphomas (MTCLs).

Project description:DNA methylation has suppressive effects on gene transcription and it is involved in a variety of physiologic processes, including development and cancer. As we and others demonstrated, Dnmt3b is a tumor suppressor in oncogene-driven lymphoid and myeloid malignancies in mice. Due to numerous activities such as methylation-dependent and independent repression and accessory functions, it is difficult to pinpoint physiological processes solely dependent on catalytic activity of Dnmt3b. By utilizing our new mouse model expressing catalytically inactive Dnmt3b at physiological levels we identified genome-wide methylation changes and aberrant gene expression profiles that are specific to catalytic activity of DNMT3b.

2020-12-30 | GSE154451 | GEO

MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with Host Cell Factor-1

Project description:MYC is an oncoprotein transcription factor that is overexpressed in the majority cancers. Although MYC itself is considered undruggable, it may be possible to inhibit MYC by targeting the co-factors it uses to drive oncogenic gene expression patterns. Here, we use loss- and gain- of function approaches to interrogate how one MYC co-factor—Host Cell Factor (HCF)-1—contributes to MYC activity in a Burkitt lymphoma setting. We identify high-confidence direct targets of the MYC–HCF-1 interaction that are regulated through a recruitment-independent mechanism, including genes that control mitochondrial function and rate-limiting steps for ribosome biogenesis and translation. We describe how these gene expression events impact cell growth and metabolism, and demonstrate that the MYC–HCF-1 interaction is essential for tumor maintenance in vivo. This work highlights the MYC–HCF-1 interaction as a focal point for development of novel anti-cancer therapies.

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DNMT3B7 disrupts embryonic development and accelerates lymphomagenesis

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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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Actionable genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma

Project description:SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we identified the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to PARP inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.

2021-07-16 | GSE180052 | GEO

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