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At least 19 recordsLinked to original sources
PubMed2025

OpTiles: an R package for adaptive tiling and methylation variability profiling.

SUMMARY: OpTiles is an R package that dynamically defines tiling windows based on the distribution of sequenced CpGs, addressing the limitations of traditional fixed-tiling approaches in targeted methylation datasets. By integrating CpG density with intra-region methylation variability, it provides a reliability metric and extended functionality for annotating, prioritizing, and interpreting complex methylation data. AVAILABILITY AND IMPLEMENTATION: OpTiles is implemented in R and source code is freely available at https://github.com/fhaive/OpTiles. Data are available on Zenodo at https://doi.org/10.5281/zenodo.16961292.

DNA Methylation↗
PubMed1991

Variable methylation of the 5'-flanking DNA of the human pro-opiomelanocortin gene.

The pro-opiomelanocortin gene is widely expressed in human tissues, although both transcriptional initiation sites and regulation appear to be tissue specific. In order to determine how promoter and enhancer choice is effected, we have studied the methylation pattern of the gene in a number of normal tissues, tumours and cell lines. Variability of this pattern was observed in the 5'-flanking DNA, particularly at the HpaII site located at -304 bp upstream from the pituitary CAP site. This site was generally methylated in tissues likely to express the predominant extrapituitary (800 nucleotide) message, while in tissues known to express the normal pituitary (1150 nucleotide) message and longer species, a tendency towards undermethylation was observed. Although the sites at which variable methylation occurs did not correspond to established binding sites for regulatory proteins, many of these regions remain to be determined and thus it is possible that methylation may be influential in the tissue-specific regulation of this gene.

DNA↗
PubMed2026

ReMeDy: A Flexible Statistical Framework for Region-Based Detection of DNA Methylation Dysregulation.

Region-based epigenome-wide association studies have demonstrated improved statistical power and biological interpretability compared with probe-wise analyses of DNA methylation data. However, most existing region-based methods characterize methylation dysregulation primarily through changes in mean methylation levels associated with a phenotype of interest. Substantial evidence indicates that phenotype-associated methylation alterations may also manifest through changes in methylation variability or through joint shifts in mean and variability. Despite this, no existing statistical framework jointly models mean-variance methylation changes in a region-based manner. We propose ReMeDy, a flexible statistical framework that uses a hierarchical likelihood approach within a generalized linear model setting to identify differentially methylated regions, variably methylated regions, and regions exhibiting joint differential and variable methylation at a genome-wide scale. Unlike existing models, ReMeDy operates directly on biologically defined co-methylated regions, allowing it to naturally capture spatial correlation inherent in DNA methylation array data, while avoiding reliance on heuristic, user-defined tuning parameters such as smoothing spans and kernel bandwidths that can substantially influence results and introduce subjectivity. Through extensive simulation studies and comprehensive benchmarking against popular models, we demonstrate that ReMeDy maintains false discovery and Type-I error rates at nominal levels while achieving consistently higher statistical power across a wide range of realistic scenarios. Application to population-level DNA methylation data further shows that ReMeDy identifies biologically meaningful regions and pathways implicated in complex human diseases that are not captured by conventional mean-based analyses alone. ReMeDy is implemented as an open-source R package and is freely available at https://github.com/SChatLab/ReMeDy.

DNA Methylation↗
PubMed1992

Methylation and sequence analysis around EagI sites: identification of 28 new CpG islands in XQ24-XQ28.

Thirty-two probes for CpG islands of the distal long arm of the human X chromosome have been identified. From a genomic library of DNA of the hamster-human cell hybrid X3000.1 digested with the rare cutter restriction enzyme EagI, 53 different human clones have been isolated and characterized by methylation and sequence analysis. The characteristic pattern of DNA methylation of CpG islands at the 5' end of genes of the X chromosome has been used to distinguish between EagI sites in CpG islands versus isolated EagI sites. The sequence analysis has confirmed and completed the characterization showing that sequences at the 5' end of known genes were among the clones defined CpG islands and that the non-CpG islands clones were mostly repetitive sequences with a non-methylated or variably methylated EagI site. Thus, since clones corresponding to repetitive sequences can be easily identified by sequencing, such libraries are a very good source of CpG islands. The methylation analysis of 28 different new probes allows to state that demethylation of CpG islands of the active X and methylation of those on the inactive X chromosome are the general rule. Moreover, the finding, in all instances, of methylation differences between male and female DNA is in very strong support of the notion that most genes of the distal long arm of the X chromosome are subject to X inactivation.

Amino Acid Sequence↗
PubMed1988

Variable DNA methylation changes during differentiation of human melanoma cells.

The DNA 5-methylcytosine content has been analyzed in the human melanoma cell line M21 at several time points after induction of differentiation by a variety of inducers. 5-Aza-2'-deoxycytidine reduces DNA methylation to about 50% of the control level and this demethylation occurs prior to the establishment of the differentiated phenotype. The DNA synthesis inhibitors cytosine arabinoside, aphidicolin, and hydroxyurea exert different effects on DNA methylation in these cells. Cytosine arabinoside induces an early DNA hypermethylation, which is however reversible and drops to the original level after 24 h. Hydroxyurea induces DNA hypermethylation after a lag period of more than 48 h and the DNA polymerase alpha inhibitor aphidicolin has no effect on the DNA methylation level. Treatment of cells with phorbol 12-myristate 13-acetate, another potent inducer of melanoma cell differentiation, does not result in a change of total DNA methylation over a period of 96 h. These results indicate that differentiation of human melanoma cells can be accompanied by variable changes of the DNA methylation pattern. These changes can be neither generally related to the differentiation process itself nor related to the effects of DNA synthesis inhibition on DNA methylation, but may more likely reflect a direct or indirect particular effect of the inducer on the DNA methylation process.

Aphidicolin↗
PubMed1985

Low expression of human histocompatibility leukocyte antigen-DR is associated with hypermethylation of human histocompatibility leukocyte antigen-DR alpha gene regions in B cells from patients with systemic lupus erythematosus.

The relationship between the expression of HLA-DR antigens and the HLA-DR alpha gene methylation was examined in systemic lupus erythematosus (SLE). Using permanent B cell lines, we found reduced DR expression in SLE. The low DR expression was correlated with high anti-DNA antibody titers in patients' sera. The amounts of DR alpha message were lower in SLE cells than in normal controls, suggesting that the low expression of DR antigens is associated with gene functions. The extent of DNA methylation was examined at five CCGG sites in the HLA-DR alpha locus. DNA from both SLE and normal cells showed variable methylation patterns. Since the DR alpha gene is a single-copy gene, such a variability is the result of assaying a mixture of transformed clones containing methylated DR alpha gene, with other clones containing unmethylated DR alpha gene. A distinctive feature of normal cells was a consistent methylation pattern: 12 normal cell lines showed exactly the same pattern. In contrast, 28 SLE cell lines showed a cell-line-specific methylation, and hypermethylation at the DR alpha locus. The hypermethylation is often associated with transcriptionally inactive genes. Thus, our results suggest that (a) B cells with hypermethylated DR genes might express no or few DR antigens; (b) the ratio of cells with differently methylated DR genes is consistent in normal individuals, while, in SLE patients, cells with hypermethylated DR genes predominate, resulting in apparently reduced DR antigen expression; and (c) the aberrant DR expression could be associated directly with immunoregulatory dysfunctions in SLE disease.

Antibodies, Antinuclear↗
PubMed1987

Tissue specific methylation of c-myc in adult chickens.

Methylation of cytosine in DNA has long been correlated with modulation of specific gene expression in eukaryotes. Methylation of the c-myc locus was examined in six tissues from adult Leghorn chickens. The c-myc locus was found to be variably methylated in all examined tissues, except blood, where erythrocytic DNA showed no evidence of significant methylation of c-myc. This is contrasted with the observed sever methylation of the beta actin locus and the generally high methylation patterns found in avian erythrocytic DNA.

Actins↗
PubMed2024

Schizophrenia is associated with altered DNA methylation variance.

Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR&#x2009;<&#x2009;0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n&#x2009;=&#x2009;644) from additional cohorts and a non-psychiatric comparison group (n&#x2009;=&#x2009;633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.

Humans↗
PubMed1988

Analysis of methylation of a human X located gene which escapes X inactivation.

The gene MIC2 is located in the pseudoautosomal region at the ends of the short arms of the X and Y chromosomes. In females MIC2 escapes X inactivation. We have analyzed the methylation pattern of MIC2 on the active X, the inactive X chromosomes, and the Y chromosome. The 5' end of the gene contains a GC rich region which is unmethylated on the active X, the inactive X and on the Y. The body of the gene is characterized by variable methylation.

Base Sequence↗
PubMed2026

Epigenetic safety of in vitro maturation in PCOS: genome-wide DNA methylation profiling of cord blood from a randomized controlled trial.

BACKGROUND: In vitro maturation (IVM) provides a safer alternative to conventional in vitro fertilization (IVF) for women with polycystic ovary syndrome (PCOS) by mitigating the risk of ovarian hyperstimulation. However, concerns persist regarding whether IVM perturbs epigenetic reprogramming in the offspring. Current evidence is constrained by candidate-gene approaches or a lack of parental controls. This study aimed to evaluate the genome-wide DNA methylation safety of IVM compared with conventional IVF using a rigorous trio-based design. METHODS: This secondary epigenetic analysis was nested within a randomized controlled trial (RCT) (ClinicalTrials.gov: NCT03463772). We included 10 nuclear families (trios), comprising five IVM-conceived and five IVF-conceived singleton offspring alongside their biological parents. Both groups utilized a uniform freeze-only single-blastocyst transfer strategy to minimize hormonal confounding. Genomic DNA from umbilical cord blood (UCB) and parental peripheral blood was analyzed using reduced representation bisulfite sequencing (RRBS). Genome-wide methylation patterns and differentially methylated regions (DMRs) were subsequently compared between the groups. RESULTS: Clinical characteristics were comparable between the IVM and IVF groups. Genome-wide analyses demonstrated high concordance in UCB methylation patterns, revealing no significant differences in global CpG methylation levels or distributions across key genomic features (promoters, CpG islands, and gene bodies). Only three rare DMRs were identified in UCB (representing&#x2009;~&#x2009;0.0001% of the genome), none of which mapped to imprinted or developmentally critical loci. Furthermore, methylation variability remained consistent between the groups. CONCLUSIONS: Our findings provide robust mechanistic evidence supporting the epigenetic safety of IVM. The remarkable stability of the neonatal methylome confirms that specific IVM conditions do not compromise early developmental programming, thereby endorsing IVM as a safe and viable alternative for women with PCOS. TRIAL REGISTRATION: ClinicalTrials.gov registry, NCT03463772. Registered on March 13, 2018.

Humans↗
PubMed1992

The Escherichia coli chromosome contains specific, unmethylated dam and dcm sites.

The Escherichia coli chromosome encodes two methylases, dam and dcm, which recognize the sequences GATC and CC(A/T)GG, respectively. Specific dam and dcm sites on the E. coli chromosome were found to be unmethylated in vivo by using pulsed-filed gel electrophoresis experiments scanning megabase regions of DNA. Some sites were totally unmethylated. The dam sites display variable methylation depending on the local sequence, and, in general, their methylation shows complex modulation by growth conditions and growth rate, suggesting multiple protection mechanisms. Sites resistant to complete dam or dcm methylation appear to be distributed throughout the chromosome. These unusual sites may identify regions of the chromosome with interesting biological functions.

Base Sequence↗
PubMed1986

DNA methylation and cancer.

The main thrusts of the arguments that aberrant DNA methylation is involved in the generation of tumor heterogeneity and progression can be summarized as follows. The methylation of specific cytosine residues in DNA is certainly an important component in multilevel gene control in eukaryotes. The discovery of CpG clusters in the flanking regions of genes and their under-methylation on housekeeping genes, except those located on inactive X-chromosomes, strongly suggests a controlling function for modification in these regions. Since methylation plays an important role in controlling normal cellular development, it follows that aberrations within this mechanism may be implicated in the abnormal gene control which characterizes cancer. Methylation patterns are not copied rigorously in rapidly dividing cells. This may be because there is normally a close coordination between DNA synthesis, DNA methylation, and DNA packaging, and changes in the timing of these processes could conceivably result in hypomethylation at some sites and de novo methylation at others. Since the greatest variability of methylation patterns is seen in nonexpressed genes, it is possible that there is a tendency for cells to activate genes when dividing in an inappropriate growth environment. The constant evolution and shuffling of methylation patterns which occur during division might play a role in the development of new phenotypes within cell populations. One might predict that selective pressures within the host would select for those cells with specific new methylation patterns allowing for the expression of genes necessary for survival in a particular environment. Many experiments have in fact shown that methylation levels and patterns and indeed methyltransferase levels (57) are altered in cancer cells. Thus, there is considerable heterogeneity within tumor populations with regard to this fundamental biological control mechanism. The fact that direct intervention by the use of 5-aza-Cyd can result in dramatic alterations in malignant potential allows this hypothesis to be tested more critically. Hopefully, the use of 5-aza-Cyd in defined systems will allow us to isolate genes which might become activated by drug treatment and which might contribute to metastatic potential. An understanding of the fundamental aspects of the enzymology and control of DNA methylation might therefore allow us to make significant inroads into understanding how heterogeneity is generated and what we might do about it.

Animals↗
PubMed1986

Differential implication of deoxyribonucleic acid methylation in rat prolactin and rat growth hormone gene expressions: a comparison between rat pituitary cell strains.

In order to assess the potential role of DNA methylation in the expression of rat PRL (rPRL) as compared to rat GH (rGH) gene, the cleavage patterns generated by the isoschizomeric restriction enzymes HpaII and MspI were examined in DNA isolated from rat pituitary cell lines producing either high levels of rPRL (GH3B6) or of rGH (GC) and in a stable variant cell strain which produces minute amounts of both hormones (GH3CDL cells). The rPRL and the rGH genes were found hypomethylated in GH3B6 and GC cells, respectively, whereas in GH3CDL cells both genes were methylated, indicating a correlation between the extent of gene methylation and the level of expression. However the use of 5-azacytidine (5-azaC), which decreases DNA methylation, suggested a variable importance of gene methylation in the control of rPRL and rGH gene expression. 5-AzaC was unable to increase rPRL production to a detectable level in GC cells, whereas the cytidine analog markedly increased rPRL production and rGH production in GH3CDL cells. Further analysis using GH3CDL cells showed that the extent of the 5-azaC-induced rPRL and rGH gene demethylation was consistent with the 5-azaC-induced increase of gene expressions. However, in these cells, the stimulation of rPRL and rGH production unexpectedly increased as a function of time elapsed after drug withdrawal. The maximal stimulation, 30-fold and 7-fold, respectively, was observed 3 weeks after a 60-h exposure to 5-azaC. This pattern suggests that other events are required for the full expression of rPRL and rGH genes in addition to their own demethylation.

Animals↗
PubMed1986

[Regulation of prolactin and growth hormone gene expression in pituitary cell culture].

The rat pituitary tumor derived cell lines of the "GH" family offer a fruitful model for studying the expressions of the prolactin (rPRL) and growth hormone (rGH) genes in basic and regulated states. In order to assess the potential role of DNA methylation in the basic expressions of rPRL and rGH genes we have used different cell strains which produce either high level of rPRL (GH3B6 cells) or of rGH (GC cells) and minute amounts of both hormones (GH3CDL cells). The cleavage patterns generated by the methylation sensitive enzymes Hpa II and Msp I indicated an inverse correlation between the extent of gene methylation and the level of expression. However the use of 5-azacytidine which decreases DNA methylation suggested a variable importance of gene methylation in the respective control of rPRL and rGH genes depending on the cell lines. In an other hand we attempted to elucidate some of the mechanisms by which thyroliberin (TRH) enhances rPRL gene transcription in GH3B6 cells. Preliminary results indicated that the persistent occupancy of the TRH receptors was required to sustain at least for the first 5 hours the increased rate of rPRL gene transcription. In addition the possible relationship between the TRH-induced acute rPRL release and the stimulation of rPRL gene transcription was investigated. The results suggested that the activators of the C kinase-mediated pathway which are actually involved in the stimulation of the acute release were not sufficient alone for eliciting the maximum TRH response at the gene level.

Animals↗
PubMed2024

Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance.

BACKGROUND: Mediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks. METHODS: We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors. RESULTS: The logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r&#x2009;=&#x2009;0.291, R2&#x2009;=&#x2009;0.033, p&#x2009;<&#x2009;0.01) and PRU (r&#x2009;=&#x2009;0.503, R2&#x2009;=&#x2009;0.210, p&#x2009;<&#x2009;0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks. CONCLUSIONS: This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03823274.

Humans↗
PubMed1991

Variable X-chromosome DNA methylation patterns detected with probe M27 beta in a series of lymphoid and myeloid malignancies.

In this study the X chromosome probe M27 beta was used to investigate DNA methylation at the DXS255 locus and hence X inactivation status and determination of tumour clonality in blood, bone marrow and biopsy tissue involved with morphologically and phenotypically defined lymphoid and myeloid disease from 14 female patients along with uninvolved bone marrow from two control individuals. Thirteen out of 16 individuals (81%) were restriction fragment length polymorphism (RFLP) heterozygous for DXS255. DNA methylation status could not be assessed in the three DXS255 homozygous individuals. In eight DXS255 heterozygous individuals clonality was clearly demonstrated using M27 beta and in six of these cases independent analysis using T cell receptor (TcR) and immunoglobulin (Ig) gene probes confirmed the presence of clonal tumour cell populations. In the two controls, polyclonality was inferred from M27 beta probe analysis. In the remaining three cases (all acute lymphoblastic leukaemia (ALL)) both DXS255 X chromosome sequences appeared to be methylated. Clonality in these cases was demonstrated by TcR or Ig monoclonal gene rearrangements. These data demonstrate the value of the M27 beta probe for determining tumour clonality in a number of cases with lymphoid and myeloid disease but indicate that there may not always be a complete correlation between DNA methylation. X inactivation status and tumour clonality in certain lymphoid neoplasms, restricting the use of this probe in clonality studies. Correlations between DNA methylation, X inactivation status and stage of normal and neoplastic T and B cell development require further investigation.

Antigens, Neoplasm↗