Disease relevance of Dnmt1

• However, these same mice developed invasive T- and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates [1].
• Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis [2].
• Inhibitors of DNA methyltransferase (Dnmt) and histone deacetylases (HDAC) synergistically activate the methylated metallothionein I gene (MT-I) promoter in mouse lymphosarcoma cells [3].
• It has been accepted that the mechanism of toxicity is due to the covalent binding between the DNA methyltransferase (Dnmt) and 5-aza-dC-substituted DNA [4].
• Genes reported to be regulated by reversible methylation were not expressed ectopically or precociously in Dnmt1-deficient mouse embryos under conditions where demethylation caused biallelic expression of imprinted genes and activated transcription of endogenous retroviruses of the IAP class [5].

Psychiatry related information on Dnmt1

• Inactivation of the DNA methyltransferase genes (Dnmt1, 3a, and 3b) was found to be lethal in mice and several human diseases (ICF and Rett syndrome) turned out to be linked to DNA methylation [6].

High impact information on Dnmt1

• Genetic experiments have defined the importance of the DNA methyltransferase Dnmt1 for the maintenance of methylation in mouse cells and its role in neoplasia [7].
• Cre-mediated deletion of Dnmt1 causes demethylation of cultured fibroblasts and a uniform p53-dependent cell death [8].
• To define the mechanism through which demethylated cells die, and to establish a paradigm for identifying genes regulated by DNA methylation, we have generated mice with a conditional allele for the maintenance DNA methyltransferase gene Dnmt1 [8].
• Our results demonstrate that loss of Dnmt1 causes cell-type-specific changes in gene expression that impinge on several pathways, including expression of imprinted genes, cell-cycle control, growth factor/receptor signal transduction and mobilization of retroelements [8].
• Mouse oocytes and preimplantation embryos lack Dnmt1 but express a variant of this protein called Dnmt1o [9].

Chemical compound and disease context of Dnmt1

• The major DNA cytosine methyltransferase isoform in mouse erythroleukemia cells, Dnmt1, exhibits potent dead-end inhibition with a single-stranded nucleic acid by binding to an allosteric site on the enzyme [10].
• Dnmt1b protein purified from a baculovirus expression system was demonstrated to be a functional DNA methyltransferase, and to have Michaelis constants for both DNA and S-adenosyl-L-methionine similar to baculovirus-expressed Dnmt1 [11].
• These results suggest that, in the presence of Dnmt1 deficiency, the effects of folate deficiency on tumor number and size may depend on the stage of adenoma development when folate deficiency is initiated [12].
• T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice [13].

Biological context of Dnmt1

• To examine whether Dnmt1 regulates reelin gene expression, we used an antisense approach to reduce (knock down) Dnmt1 expression [14].
• These data point to a direct role of Dnmt1 in the restoration of epigenetic information during DNA repair [15].
• More importantly, the Dnmt1 knockdown blocked the methionine-induced reelin and GAD67 mRNA down-regulation [14].
• Methylation caused the activation of the silent Igf2 allele in wild-type and Dnmt1 knockout cells, leading to biallelic Igf2 expression [16].
• 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 [16].

Anatomical context of Dnmt1

• Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b [17].
• A variant of Dnmt1, designated Dnmt1o, accumulates in oocyte nuclei during the follicular growth phase [18].
• Both mRNA and protein levels of Dnmt1 and Dnmt3b were increased in the thymus and the liver of p53-deficient mice [19].
• Treatment with trichostatin A, a specific inhibitor of histone deacetylase, increased Dnmt1 promoter activity in G0/G1-arrested NIH 3T3 cells [20].
• Dnmt1p is found only in pachytene spermatocytes, whereas Dnmt1o is specific to oocytes and preimplantation embryos [21].

Associations of Dnmt1 with chemical compounds

• DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b cooperatively regulate cytosine methylation in CpG dinucleotides in mammalian genomes, providing an epigenetic basis for gene silencing and maintenance of genome integrity [17].
• Dnmt3a purified through glycerol gradient centrifugation was also associated with a histone H3 methyltransferase (HMTase) activity whereas purified Dnmt3b/Dnmt1 was devoid of any HMTase activity [22].
• DNA cytosine methyltransferase 1 (Dnmt1), which preserves epigenetic signals by completing the methylation of hemimethylated DNA after DNA replication, has been indicated as one of these PCNA binding proteins by a previous work [23].
• In order to define which member of the Dnmt family plays a dominant role in the cytotoxicity, we examined the effect of 5-aza-dC on cell growth and apoptosis in various Dnmt null mutant embryonic stem (ES) cells [4].
• Dnmt2 is a candidate for the activity that methylates newly integrated retroviral DNA and maintains trace levels of 5-methylcytosine in the DNA of embryonic stem cells homozygous for null mutations in Dnmt1 [24].

Enzymatic interactions of Dnmt1

• An ODN binding site in native MTase mRNA was identified that was cleaved by endogenous RNase H with an efficiency of 85% in the extracts [25].

Regulatory relationships of Dnmt1

• As a result, both Dnmt1(-/-) CD4 and CD8 T cells expressed high and comparable amounts of Th2 cytokines [26].
• Dnmt1o is a variant form of the somatically expressed Dnmt1 cytosine methyltransferase that is synthesized and stored in the oocyte cytoplasm and trafficks to the eight-cell nucleus during preimplantation development, where it maintains DNA methylation patterns on alleles of imprinted genes [27].

Other interactions of Dnmt1

• 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 [16].
• Therefore, Dnmt1 and Dnmt3a/3b share targets in CpG islands [28].
• To elucidate how DNA methyltransferases (Dnmts) participate in methylation of the genomic components, we investigated the genome-wide DNA methylation pattern of the T-DMRs with Dnmt1-, Dnmt3a-, and/or Dnmt3b-deficient ES cells by restriction landmark genomic scanning (RLGS) [28].
• The reduced Dnmt1 mRNA and protein were accompanied by increased reelin mRNA expression [14].
• Mouse Dnmt1 is a 180 kDa protein comprising the N-terminal regulatory domain, which covers 2/3 of the molecule, and the rest C-terminal catalytic domain [29].

Analytical, diagnostic and therapeutic context of Dnmt1

• Results of the Western blot, immunofluorescence microscopy, RT-PCR, and quantitative real time RT-PCR analysis demonstrated that Dnmt1 and Dnmt3b expression increased significantly (P < 0.001) in drug resistant cells when compared with wild type cells [30].
• Increased expression of Dnmt3b was observed at days 5 and 14, followed by increased expression of Dnmt1 and Dnmt3a at day 30, as evaluated by real-time RT-PCR [31].
• RESULTS: Dnmt1 can be readily isolated from nuclear extracts by PCNA affinity chromatography [23].
• Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels [32].
• We identified an alternative Dnmt1 transcript in skeletal muscle by Northern blot analysis and cloned the corresponding cDNA by rapid amplification of cDNA ends and reverse transcription-PCR [33].

References