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PubMed1996

H1-H1 cross-linking efficiency depends on genomic DNA methylation.

Oligonucleosomal DNA preparations from condensed-inactive chromatin were examined, before and after artificial methylation by bacterial SssI methylase, for their ability to allow cooperative H1-H1 interactions under conditions of different ionic strength. Our results support the conclusion that, within the highly methylated genomic DNA, there are some CpG's whose unmethylated state is critical for chromatin folding. Circular dichroism spectra indicate that artificial overmethylation of native oligonucleosomal DNA reduces its efficiency in inducing an ordered conformation of H1 histone. Temperature melting profiles confirm on the other hand that the native and the artificially overmethylated forms of oligonucleosomal DNA are both able to bind H1 histone.

Circular Dichroism↗

PubMed2005

Effect of acute hyperhomocysteinemia on methylation potential of erythrocytes and on DNA methylation of lymphocytes in healthy male volunteers.

Homocysteine is a precursor of S-adenosylmethionine (AdoMet) and a metabolite of S-adenosylhomocysteine (AdoHcy). The ratio of AdoMet to AdoHcy, defined as the methylation potential (MP), indicates the flow of methyl groups within the cells. Chronic elevations of total homocysteine (tHcy) in plasma correlate with increased AdoHcy concentrations, decreased MP, and impaired DNA methylation. However, the influence of acute hyperhomocysteinemia on MP is unknown. We induced acute hyperhomocysteinemia in 14 healthy volunteers by oral administration of l-homocysteine (65.1 micromol/kg body wt) in an open, randomized, placebo-controlled two-period crossover study. The kinetics of tHcy in blood and urine, MP in blood, and global DNA methylation in lymphocytes were studied systematically during 48 h. Plasma tHcy concentrations reached a peak at 34 +/- 11 min after an oral load with l-homocysteine and decreased with a half-life of 257 +/- 41 min (means +/- SD). Only 2.3% of the homocysteine dose were recovered in urine. AdoHcy concentrations and MP in whole blood and erythrocytes were not affected by the oral homocysteine load. Furthermore, global DNA methylation in lymphocytes did not change under these conditions. We found no difference between the genotypes of 5,10-methylenetetrahydrofolate reductase in response to the homocysteine load. However, AdoMet content in erythrocytes was significantly higher in the C677T carriers (CT; n = 7) compared with the CC genotype (n = 7). Although chronic elevation of tHcy has been shown to affect MP and DNA methylation, acute elevation of plasma tHcy above 20 micromol/l for 8 h is not sufficient to change MP and to induce DNA hypomethylation in lymphocytes.

Adult↗

PubMed1998

Trichostatin A causes selective loss of DNA methylation in Neurospora.

Both DNA methylation and hypoacetylation of core histones are frequently associated with repression of gene expression. Possible connections between these processes were investigated by taking advantage of genes controlled by methylation in Neurospora crassa. Trichostatin A (TSA), a potent inhibitor of histone deacetylase, derepressed a copy of hph that was repressed by DNA methylation which resulted from repeat-induced point mutation (RIP) acting on sequences flanking hph. Derepression by TSA was comparable to derepression by the inhibitor of DNA methylation, 5-azacytidine. TSA treatment also repressed an allele of am whose expression depends on methylation of an adjacent transposon, Tad. DNA methylation in the hph and Tad/am regions was greatly reduced by TSA treatment. TSA also caused hypomethylation of other methylated alleles of am generated by RIP. In contrast, TSA did not affect methylation of several other methylated genomic sequences examined, including the nucleolar rDNA and the inactivated transposon PuntRIP1. Several possible models are discussed for the observed selective demethylation induced by TSA. The implication that acetylation of chromatin proteins can directly or indirectly control DNA methylation raises the possibility that connections between protein acetylation and DNA methylation result in self-reinforcing epigenetic states.

DNA Methylation↗

PubMed2002

Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring.

This study was designed to determine if maternal dietary methyl supplements increase DNA methylation and methylation-dependent epigenetic phenotypes in mammalian offspring. Female mice of two strains were fed two levels of dietary methyl supplement or control diet prior to and during pregnancy. Offspring of these mice vary in phenotype, which is epigenetically determined and affects health and 2-y survival. Phenotype and DNA methylation of a long terminal repeat (LTR) controlling expression of the agouti gene were assayed in the resulting offspring. Methyl supplements increase the level of DNA methylation in the agouti LTR and change the phenotype of offspring in the healthy, longer-lived direction. This shows that methyl supplements have strong effects on DNA methylation and phenotype and are likely to affect long-term health. Optimum dietary supplements for the health and longevity of offspring should be intensively investigated. This should lead to public policy guidance that teaches optimal, rather than minimal, dose levels of maternal supplements.

Animals↗

PubMed1990

Transcription inhibition of SV40 by in vitro DNA methylation.

SV40 DNA was methylated in vitro with prokaryotic or eukaryotic DNA cytosine-5-methyltransferases and the inhibition of transcription by methylation was studied in Xenopus oocytes. Methylation with the prokaryotic HhaI or HpaII methyltransferases did essentially not inhibit transcription of SV40. Methylation with a rat liver methyltransferase led only to minor inhibition of the SV40 early genes, but to a complete shut shut off of the SV40 late genes. Partial methylation showed that methylation of both, the regulatory region and the 5' end of the SV40 late genes, was necessary for the effect on transcription. The TK gene could be inactivated by eukaryotic methylation of either the promoter and the first 50 nucleotides of the gene or the 3' rest of the gene. Insertion of the SV40 enhancer, not containing methylatable CpGs, into the TK upstream region, had no influence on the inhibition of TK gene transcription by methylation.

Animals↗

PubMed2001

Alteration of DNA methylation in gastrointestinal carcinogenesis.

DNA methylation is the main epigenetic modification in humans. The methylation of promoter inhibits the transcription in most genes. In normal tissues, isolated CpG dinucleotides in bulk chromatin are often methylated, whereas cytosines in CpG islands are unmethylated. In neoplasms including gastrointestinal cancer, this pattern of methylation is commonly reversed. The alteration of DNA methylation plays a key role in the process of carcinogenesis. The gastrointestinal carcinogenesis is suggested to be associated with the decrease of total genomic DNA methylation; hypomethylation of certain specific oncogenes such as c-myc, c-Ha-ras, c-fos and alpha-fetoprotein; and hypermethylation of the promoter of some tumor suppressor genes containing p16(INK4A), E-cadherin and hMLH1 genes. This review focuses on the analysis methods for methylation, studies for aberrant DNA methylation in gastrointestinal carcinogenesis, and the intervention changing methylation, including the treatment of 5-azacytidine, supplement of folate and gene therapy.

Adaptor Proteins, Signal Transducing↗

PubMed1982

DNA methylation in mouse cells in culture as measured by restriction enzymes.

Methylation of DNA in normal mouse cultured 3T3 cells and in their virally or chemically transformed derivatives was studied. DNA methylation was studied by restriction with HpaII, MspI, or HpaII plus MspI. DNA from the chemically transformed cells was cleaved about twice as often with HpaII than was the DNA of normal and virally transformed cells. Digests with MspI and HpaII plus MspI were identical in all cell lines studied. Densitometry of the restriction patterns allowed an estimate of total DNA methylation from the weight average lengths. The chemically transformed cell line showed 25% reduction in methylation compared to the other cell lines. Southern blot hybridization using satellite DNA showed that these sequences followed a pattern of modification similar to that of total DNA.

Animals↗

PubMed2006

Genome-wide analysis of DNA methylation changes in human malignancies.

DNA methylation is an epigenetic modification of the DNA sequence and thus does not change the genetic code but affects chromosomal stability and gene expression. DNA methylation patterns are heritable and can be passed on to the daughter cell. In this review, we briefly summarize our current knowledge on normal DNA methylation patterns and move on to discuss the current state of the field with respect to altered DNA methylation in cancer. We make a special attempt to address current questions relating to genome-wide DNA methylation patterns. Since DNA methylation is used as a therapeutic target in clinical studies, it is of utmost importance to define potential target sequences that could be used as diagnostic or prognostic markers. We conclude the review by outlining possible scenarios that may explain tumor type-specific DNA methylation patterns described by assays evaluating genome-wide levels of DNA methylation.

CpG Islands↗

PubMed2000

Genomic DNA methylation decreases in response to moderate folate depletion in elderly women.

BACKGROUND: Methylation of genomic DNA is dependent on an adequate supply of folate coenzymes. Previous data support the hypothesis that abnormal DNA methylation plays an integral role in carcinogenesis. To date, no studies assessing the effect of inadequate folate status on DNA methylation in older women (aged >63 y) have been reported. OBJECTIVE: The effect of moderate folate depletion followed by folate repletion on leukocyte genomic DNA methylation was investigated in elderly women (aged 60-85 y) to evaluate whether DNA methylation could be used as a functional indicator of folate status. DESIGN: Healthy, postmenopausal women (n = 33) consumed a moderately folate-depleted diet (118 microg folate/d) for 7 wk, followed by 7 wk of folate repletion with 200 or 415 microg/d, each provided as 2 different dietary treatments for a total of 4 treatment groups (n = 30). Leukocyte DNA methylation was determined on the basis of the ability of DNA to incorporate [(3)H]methyl groups from labeled S:-adenosylmethionine in an in vitro assay. RESULTS: Incorporation of [(3)H]methyl groups increased significantly (P: = 0.0025) in response to folate depletion, suggesting undermethylation of DNA. No significant changes were detected in [(3)H]methyl incorporation in any group over the 7-wk repletion period compared with postdepletion values. CONCLUSIONS: DNA methylation status may be used as a functional indicator of moderately depleted folate status. The slow response to the repletion diets observed suggests that normalization of DNA methylation after moderate folate depletion may be delayed in older women.

Aged↗

PubMedDate not supplied

[Possible origin and evolution of enzymatic methylation of eukaryotic DNA. Methylation of cytosine residues in 3 palindromic families: RYRY, YYRR, and YYRYRR].

Data on nearest neighbors of 5-methylcytosine residues in eukaryotic DNA were analyzed. It was found that the methylation sites C*G and C*NG may be located in three palindromic families: RYRY, YYRR and YYRYRR. It was shown that all the methylated sequences in these DNAs can appear as a result of 5-MeC----T substitutions, proceeding by deamination of 5-MeC residues in the "prototype" sites of each of these families: G*CGC*, C*C*GG and C*C*GCGG. The multiplicity of DNA-methyltransferases in eukaryotic cells and their evolutionary origin from prokaryotic type II methylases, recognizing analogous sequences in DNA, are discussed.

5-Methylcytosine↗

PubMed2003

DNA methylation and autoimmune disease.

DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well.

Animals↗

PubMed1983

Azacytidine-induced tumorigenesis of CHEF/18 cells: correlated DNA methylation and chromosome changes.

5-Azacytidine (azaC), a drug that induces decreased methylation of DNA in mammalian cells, was shown previously to induce differentiation of mesenchymal cell types in CHEF/18 cells (Chinese hamster embryo fibroblasts). This paper describes the effectiveness of azaC in inducing tumorigenicity in CHEF/18 cells, previously shown to be nontumorigenic stable diploids. A short exposure of growing cells to 3 microM azaC induced tumor-forming ability in CHEF/18 stem cells. Pre-adipocyte clones and subclones derived from CHEF/18 by prior treatment with azaC were also found to be tumorigenic. Pre-adipocytes previously induced by insulin in the absence of azaC were mostly nontumorigenic, but one clone produced tumors and gave rise to both tumorigenic and nontumorigenic subclones. Karyotype analysis of 41 clones and subclones from azaC-induced and insulin-induced pre-adipocytes revealed a complete correlation between tumor-forming ability and the presence of trisomy for chromosome 3q. In addition, the tumorigenic and tumor-derived lines were demethylated at specific C-C-G-G sites in the preproinsulin, Ha-ras, and Ki-ras genes as revealed by blot hybridization to Msp I- and Hpa II-digested DNAs, whereas the nontumorigenic lines resembled the CHEF/18 controls. This three-way correlation between tumorigenicity, trisomy for 3q, and specific demethylation suggests that decreased DNA methylation may be involved both in differentiation and in tumorigenicity, and that azaC may induce chromosomal aberrations as well as altering DNA methylation.

Adipose Tissue↗

PubMed2004

Conservation of DNA methylation in dipteran insects.

DNA methylation is a central mechanism of epigenetic regulation. Whereas vertebrate DNA methylation requires at least four different DNA methyltransferases, Drosophila melanogaster only utilizes a single, Dnmt2-like enzyme. This profound difference has raised the question of the evolutionary significance of the Drosophila methylation system. We have now identified Dnmt2-like open reading frames in the genome sequences of Drosophila pseudoobscura and Anopheles gambiae. These genes represent the only candidate DNA methyltransferases in their respective genomes. Consistent with a catalytic activity of Dnmt2 proteins, we could also demonstrate low but significant levels of DNA methylation in genomic DNA from these species. Lastly, we were also able to detect highly conserved Dnmt2-like open reading frames and concomitant DNA methylation in several additional Drosophila species, which suggests that Dnmt2-mediated DNA methylation has been conserved over a considerable evolutionary distance.

Amino Acid Sequence↗

PubMed2026

FUSE: data-driven functional segmentation of DNA methylation data.

SUMMARY: DNA methylation (DNAm) of neighbouring CpG sites is highly correlated, making DNAm function in terms of blocks. DNAm patterns and functionality are linked to both chromatin structure of DNA and gene regulation. Defining biologically meaningful DNA methylation blocks from whole-genome bisulfite sequencing (WGBS) data remains challenging, as most existing methods rely on fixed genomic windows rather than the observed methylation pattern. We present FUSE, a data-driven segmentation method that captures intrinsic methylation segments directly from WGBS data by jointly analyzing multiple samples. FUSE identifies spatially homogeneous methylation blocks shared across the input cohort while allowing different methylation states across samples. Applied to 61 WGBS samples from the ENCODE database, FUSE identified segments which overlap significantly with promoters, enhancers, and repetitive elements. FUSE was able to recover the true segment breakpoints in synthetic data with high sensitivity under increased levels of noise. As such, FUSE facilitates post hoc methylation analyses by aggregating coherent CpG sites into candidate segments for downstream differential methylation testing or other comparative studies. AVAILABILITY AND IMPLEMENTATION: FUSE is implemented as an R-package methFuse, available at https://github.com/holmsusa/methFuse and https://cran.r-project.org/package=methFuse. A GenomeSpy visualization of the data is available at https://csbi.ltdk.helsinki.fi/p/fuse_encode_gs/.

DNA Methylation↗

PubMed2005

Gardening the genome: DNA methylation in Arabidopsis thaliana.

DNA methylation has two essential roles in plants and animals - defending the genome against transposons and regulating gene expression. Recent experiments in Arabidopsis thaliana have begun to address crucial questions about how DNA methylation is established and maintained. One cardinal insight has been the discovery that DNA methylation can be guided by small RNAs produced through RNA-interference pathways. Plants and mammals use a similar suite of DNA methyltransferases to propagate DNA methylation, but plants have also developed a glycosylase-based mechanism for removing DNA methylation, and there are hints that similar processes function in other organisms.

Arabidopsis↗

PubMed1984

5-aza-2'-deoxycytidine therapy in patients with acute leukemia inhibits DNA methylation.

The effect of 5-aza-2'-deoxycytidine (5-AZA-dCyd) on methylation of DNA in blood leukemic cells from patients with lymphoid and myeloid leukemia was investigated. After treatment with continuous infusion of 5-AZA-dCyd (1.0 mg/kg/h) the blood leukemic cells were isolated and incubated in vitro with [6-3H]deoxycytidine and the incorporation of radioactivity into 5-methylcytosine and cytosine of DNA determined. 5-AZA-dCyd produced greater than 70% inhibition of DNA methylation in the leukemic cells. The antileukemic action of 5-AZA-dCyd may be related to the inhibition of DNA methylation.

Azacitidine↗

PubMed2024

Transgenerational increases in DNA methylation in Arabidopsis plants defective in active DNA demethylation.

Spontaneous gain or loss of DNA methylation occurs in plant and animal genomes, and DNA methylation changes can lead to meiotically stable epialleles that generate heritable phenotypic diversity. However, it is unclear whether transgenerational epigenetic stability may be regulated by any cellular factors. Here, we examined spontaneously occurring variations in DNA methylation in wild-type and ros1 mutant Arabidopsis plants that were propagated for ten generations from single-seed descent. We found that the ros1 mutant, which is defective in active DNA demethylation, showed an increased transgenerational epimutation rate. The ros1 mutation led to more spontaneously gained methylation than lost methylation at individual cytosines, compared to the wild type which had similar numbers of spontaneously gained and lost methylation cytosines. Consistently, transgenerational differentially methylated regions were also biased toward hypermethylation in the ros1 mutant. Our results reveal a genetic contribution of the ROS1 DNA demethylase to transgenerational epigenetic stability and suggest that ROS1 may have an unexpected surveillance function in preventing transgenerational DNA methylation increases.

Arabidopsis↗

PubMed1999

Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation.

Methylation of DNA at the dinucleotide CpG is essential for mammalian development and is correlated with stable transcriptional silencing. This transcriptional silencing has recently been linked at a molecular level to histone deacetylation through the demonstration of a physical association between histone deacetylases and the methyl CpG-binding protein MeCP2 (refs 4,5). We previously purified a histone deacetylase complex from Xenopus laevis egg extracts that consists of six subunits, including an Rpd3-like deacetylase, the RbA p48/p46 histone-binding protein and the nucleosome-stimulated ATPase Mi-2 (ref. 6). Similar species were subsequently isolated from human cell lines, implying functional conservation across evolution. This complex represents the most abundant form of deacetylase in amphibian eggs and cultured mammalian cells. Here we identify the remaining three subunits of this enzyme complex. One of them binds specifically to methylated DNA in vitro and molecular cloning reveals a similarity to a known methyl CpG-binding protein. Our data substantiate the mechanistic link between DNA methylation, histone deacetylation and transcriptional silencing.

Adenosine Triphosphatases↗