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Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [MBD-seq]

ABSTRACT: Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depltion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54842 | GEO | 2014/10/20

SECONDARY ACCESSION(S): PRJNA237802

REPOSITORIES: GEO

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Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [MBD-seq]

Project description:Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depltion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous. NCCIT cells were transfected with siRNAs against DNMT3B and a no-target control. Genomic DNA was extracted, and subsequently applied to affinity MBD-bound magnetic beads (Ribomed) to enrich methylated DNA sequences.

2014-10-20 | E-GEOD-54842 | biostudies-arrayexpress

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [gene expression]

2014-10-20 | E-GEOD-54841 | biostudies-arrayexpress

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [methylation]

2014-10-20 | GSE54840 | GEO

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [gene expression]

2014-10-20 | GSE54841 | GEO

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [methylation]

Project description:Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depletion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous. Overall, 27 samples were analyzed using the Infinium HumanMethylation450 BeadChip. 19 samples include NCCIT cells treated with various siRNAs targeting specific DNA methyltransferases. For the samples labeled biological replicate 1, NTC-1 serves as the control. Two additional biological replicates were analyzed for the siDNMT1, siDNMT3B, and si3B+3L condition; NTC-2 serves as the control for these samples. Six samples include HCT116 WT and various derivatives with alternative expression of DNMT1 and/or DNMT3B; WT serves as the control. Two samples include the undifferentiated (UD) and 7-day differentiated (DF) NCCIT cells; UD serves as the control.

2014-10-20 | E-GEOD-54840 | biostudies-arrayexpress

Profiling of Chromatin States in a Human Cancer Cell Line

Project description:DNA methylation mediated by the combined action of three DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, is essential for mammalian development and is also a major contributor to transformation. To elucidate how DNA methylation is targeted, we map the genome-wide localization of all DNMTs and methylation, and examine relationships between these markers and histone modifications and nucleosome structure. Our findings reveal a strong link between DNA methylation/DNMTs and transcribed loci and that these marks exhibit both overlapping and unique localization patterns. Comparisons with the epigenome of embryonic stem cells demonstrate that DNMT binding is associated with transformation-associated changes in methylation. Taken together, this study sheds important new light on determinants of DNA methylation and how it may become disrupted in cancer cells. Examination of different marks in undifferentiated and differentiatial NCCIT cells

2012-10-19 | E-GEOD-38937 | biostudies-arrayexpress

Active DNA Demethylation by DNMT3A and DNMT3B - Mechanistic Aspect and In Vivo Evidence

Project description:The DNA methylation program is at the bottom layer of the epigenetic regulatory cascade of vertebrate development. While the methylation at C-5 position of the cytosine (C) residues on the vertebrate genomes is achieved through the catalytic activities of the DNA methyltransferases (DNMTs), the conversion of the methylated cytosine (5mC) could be accomplished by the combined actions of the TET enzyme and DNA repair. Interestingly, it has been found recently that the mouse and human DNMTs also possess active DNA demethylation activity in vitro in a Ca2+- and redox condition-dependent manner. We report here the study of tracking down the fate of the methyl group removed from 5mC on DNA during in vitro demethylation reaction by mouse de novo DNMTs, i.e. DNMT3A and DNMT3B. Remarkably, the methyl group becomes covalently linked to the catalytic cysteines utilized by the two de novo DNMTs in their DNA methylation reactions. Thus, the forward and reverse reactions of DNA methylations by the DNMTs may utilize the same cysteine residue(s) as the active site despite of their distinctive pathways. Secondly, we demonstrate that active DNA demethylation of a heavily methylated GFP reporter plasmid by ectopically expressed DNMT3A or DNMT3B occurs in vivo in transfected human HEK 293 cells in culture. Furthermore, the extent of DNA demethylation by the DNMTs in this cell-based system is affected by Ca2+ homeostasis as well as by mutation of their putative active cysteines. These findings substantiate the roles of the vertebrate DNMTs as double-edged swords in DNA methylation-demethylation in vitro as well as in a cellular context.

2022-02-24 | PXD003401 | Pride

Pivotal role for S-nitrosylation of DNA methyltransferase in epigenetic regulation

Project description:DNMTs catalyze the methylation of cytosine with SAM. DNA methylation affects key cellular processes by regulating gene expression, thus serving a variety of physiological and pathophysiological roles. However, the chemical mechanisms of DNA methylation by which its enzymatic activity is regulated have not been fully elucidated. We found that a critical cysteine residue in DNMT is the target of protein S-nitrosylation, leading to the attenuation of DNMT enzymatic activity and consequent aberrant regulation of gene expression during neoplastic cell proliferation. Our results demonstrate that de novo DNA methylation mediated by DNMT3 is regulated by NO, which is involved in tumor formation.

2023-03-11 | PXD039437 | Pride

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome.

| S-EPMC4254561 | biostudies-literature

Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice

Project description:DNA methylation is generally known to inactivate gene expression. The DNA methyltransferases (DNMTs), DNMT3A and DNMT3B, catalyze somatic cell lineage-specific DNA methylation, while DNMT3A and DNMT3L catalyze germ cell lineage-specific DNA methylation. How such lineage- and gene-specific DNA methylation patterns are created remains to be elucidated. To better understand the regulatory mechanisms underlying DNA methylation, we generated transgenic mice that constitutively expressed DNMT3A and DNMT3L, and analyzed DNA methylation, gene expression, and their subsequent impact on ontogeny. All transgenic mice were born normally but died within 20 weeks accompanied with cardiac hypertrophy. Several genes were repressed in the hearts of transgenic mice compared with those in wild-type mice. CpG islands of these downregulated genes were highly methylated in the transgenic mice. This abnormal methylation occurred in the perinatal stage. Conversely, mono-allelic DNA methylation at imprinted loci was faithfully maintained in all transgenic mice, except H19. Thus, the loci preferred by DNMT3A and DNMT3L differ between somatic and germ cell lineages.

2019-02-15 | GSE126566 | GEO

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