The DNA methylation landscape of five pediatric-tumor types

Fewer DNA mutations have been identified in pediatric tumors than adult tumors, suggesting that alternative tumorigenic mechanisms, including aberrant DNA methylation, may play a prominent role in pediatric tumors. Methylation is an epigenetic process of regulating gene expression in which methyl groups are attached to DNA molecules, often in promoter regions. In Wilms tumors and acute myeloid leukemias, increased levels of epigenetic silencing have been associated with worse patient outcomes. However, to date, researchers have studied methylation primarily in adult tumors and for specific genes but not on a pan-pediatric cancer scale. We addressed these gaps first by aggregating methylation data from 309 noncancerous samples and establishing baseline expectations for each gene. Even though these samples represent diverse tissue types and population ancestral groups, methylation levels were highly consistent for most genes. Second, we compared tumor methylation levels against these baseline values for five pediatric cancer types--Wilms tumors, clear cell sarcomas of the kidney, rhabdoid tumors, neuroblastomas, and osteosarcomas. Hypermethylation was more common than hypomethylation--as many as 11.8% of genes were hypermethylated in a given tumor, compared to a maximum of 4.8% for hypomethylated genes. For each cancer type, genes with the highest variance exhibited consistently divergent methylation patterns for distinct patient subsets. We evaluated whether genomic and epigenomic abnormalities contribute to pediatric tumorigenesis in a mutually exclusive manner but did not find evidence of this phenomenon. Furthermore, even though oncogenes are commonly upregulated in tumors, and tumor-suppressor genes are commonly downregulated in tumors, we did not find statistical evidence that methylation drives such patterns on a broad scale in pediatric tumors.

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A role for poly(ADP-ribosyl)ation in DNA methylation

Biochemistry and Cell Biology ◽

10.1139/o03-050 ◽

2003 ◽

Vol 81 (3) ◽

pp. 197-208 ◽

Cited By ~ 10

Author(s):

Giuseppe Zardo ◽

Anna Reale ◽

Giovanna De Matteis ◽

Serena Buontempo ◽

Paola Caiafa

Keyword(s):

Dna Methylation ◽

Gene Silencing ◽

Control Mechanism ◽

Epigenetic Modification ◽

Housekeeping Genes ◽

Promoter Regions ◽

Epigenetic Events ◽

Aberrant Dna Methylation ◽

Methylation Patterns ◽

Histone Methylation And Acetylation

The aberrant DNA methylation of promoter regions of housekeeping genes leads to gene silencing. Additional epigenetic events, such as histone methylation and acetylation, also play a very important role in the definitive repression of gene expression by DNA methylation. If the aberrant DNA methylation of promoter regions is the starting or the secondary event leading to the gene silencing is still debated. Mechanisms controlling DNA methylation patterns do exist although they have not been ultimately proven. Our data suggest that poly(ADP-ribosyl)ation might be part of this control mechanism. Thus an additional epigenetic modification seems to be involved in maintaining tissue and cell-type methylation patterns that when formed during embryo development, have to be rigorously conserved in adult organisms.Key words: DNA methylation, chromatin, poly(ADP-ribosyl)ation.

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Age-related disturbances in DNA (hydroxy)methylation in APP/PS1 mice

Translational Neuroscience ◽

10.1515/tnsci-2018-0028 ◽

2018 ◽

Vol 9 (1) ◽

pp. 190-202 ◽

Cited By ~ 3

Author(s):

Leonidas Chouliaras ◽

Roy Lardenoije ◽

Gunter Kenis ◽

Diego Mastroeni ◽

Patrick R. Hof ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Dna Methylation ◽

Brain Aging ◽

Wild Type ◽

Dna Hydroxymethylation ◽

Quantitative Immunohistochemistry ◽

Age Related ◽

Aberrant Dna Methylation ◽

Methylation Patterns ◽

Age Related Changes

Abstract Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer’s disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice.

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Atherosclerosis risk factors can impose aberrant DNA methylation patterns: a tale of traffic and homocysteine

Current Opinion in Lipidology ◽

10.1097/mol.0b013e3283309928 ◽

2009 ◽

Vol 20 (5) ◽

pp. 448-449 ◽

Cited By ~ 13

Author(s):

Gertrud Lund ◽

Silvio Zaina

Keyword(s):

Risk Factors ◽

Dna Methylation ◽

Atherosclerosis Risk ◽

Atherosclerosis Risk Factors ◽

Aberrant Dna Methylation ◽

Methylation Patterns

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Fetal and Neonatal Exposure to the Endocrine Disruptor Methoxychlor Causes Epigenetic Alterations in Adult Ovarian Genes

Endocrinology ◽

10.1210/en.2009-0499 ◽

2009 ◽

Vol 150 (10) ◽

pp. 4681-4691 ◽

Cited By ~ 91

Author(s):

Aparna Mahakali Zama ◽

Mehmet Uzumcu

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Ovarian Function ◽

Endocrine Disrupting Chemicals ◽

Neonatal Exposure ◽

Dna Hypermethylation ◽

Promoter Regions ◽

Altered Expression ◽

Arbitrarily Primed Pcr ◽

Methylation Patterns

Abstract Exposure to endocrine-disrupting chemicals during development could alter the epigenetic programming of the genome and result in adult-onset disease. Methoxychlor (MXC) and its metabolites possess estrogenic, antiestrogenic, and antiandrogenic activities. Previous studies showed that fetal/neonatal exposure to MXC caused adult ovarian dysfunction due to altered expression of key ovarian genes including estrogen receptor (ER)-β, which was down-regulated, whereas ERα was unaffected. The objective of the current study was to evaluate changes in global and gene-specific methylation patterns in adult ovaries associated with the observed defects. Rats were exposed to MXC (20 μg/kg·d or 100 mg/kg·d) between embryonic d 19 and postnatal d 7. We performed DNA methylation analysis of the known promoters of ERα and ERβ genes in postnatal d 50–60 ovaries using bisulfite sequencing and methylation-specific PCRs. Developmental exposure to MXC led to significant hypermethylation in the ERβ promoter regions (P < 0.05), whereas the ERα promoter was unaffected. We assessed global DNA methylation changes using methylation-sensitive arbitrarily primed PCR and identified 10 genes that were hypermethylated in ovaries from exposed rats. To determine whether the MXC-induced methylation changes were associated with increased DNA methyltransferase (DNMT) levels, we measured the expression levels of Dnmt3a, Dnmt3b, and Dnmt3l using semiquantitative RT-PCR. Whereas Dnmt3a and Dnmt3l were unchanged, Dnmt3b expression was stimulated in ovaries of the 100 mg/kg MXC group (P < 0.05), suggesting that increased DNMT3B may cause DNA hypermethylation in the ovary. Overall, these data suggest that transient exposure to MXC during fetal and neonatal development affects adult ovarian function via altered methylation patterns.

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DNA methylation patterns–based subtype distinction and identification of soft tissue sarcoma prognosis

10.21203/rs.3.rs-26298/v1 ◽

2020 ◽

Author(s):

Zhengyuan Wu ◽

Miao Yu ◽

Jing-yuan Fan ◽

Zhen-pei Wen ◽

Tian-yu Ren ◽

...

Keyword(s):

Dna Methylation ◽

Soft Tissue ◽

Clinical Features ◽

Soft Tissue Sarcomas ◽

Survival Prediction ◽

Biological Functions ◽

Promoter Regions ◽

Patient Prognosis ◽

Selection Operator ◽

Methylation Patterns

Abstract Background: Soft tissue sarcomas (STSs) are heterogeneous at the clinical with a variable tendency of aggressive behavior. Methods: In this study, we constructed a specific DNA methylation-based classification to identify the distinct prognosis-subtypes of STSs based on the DNA methylation spectrum from the TCGA database.Results: Eventually, samples were clustered into four subgroups, and their survival curves were distinct from each other. Meanwhile, the samples in each subgroup reflected differentially in several clinical features. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also conducted on the genes of the corresponding promoter regions of the above‐described specific methylation sites, revealing that these genes were mainly concentrated in certain cancer‑associated biological functions and pathways. In addition, we calculated the differences among clustered methylation sites and performed the specific methylation sites with LASSO algorithm. The selection operator algorithm was employed to derive a risk signature model, and a prognostic signature based on these methylation sites performed well for risk stratification in STSs patients. At last, a nomogram consisted of clinical features and risk score was developed for the survival prediction. Conclusion: In conclusion, this study declares that DNA methylation-based STSs subtype classification is highly relevant for future development of personalized therapy as it identifies the prediction value of patient prognosis.

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The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

Cells ◽

10.3390/cells9092004 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2004 ◽

Cited By ~ 1

Author(s):

Terisha Ghazi ◽

Thilona Arumugam ◽

Ashmika Foolchand ◽

Anil A. Chuturgoon

Keyword(s):

Dna Methylation ◽

Bioactive Compounds ◽

Epigenetic Modification ◽

Bioactive Molecules ◽

Methyl Donors ◽

Food Borne ◽

One Carbon Metabolism ◽

Aberrant Dna Methylation ◽

Methylation Patterns ◽

The Impact

Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.

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DNA Methylation and Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2004.07.151 ◽

2004 ◽

Vol 22 (22) ◽

pp. 4632-4642 ◽

Cited By ~ 703

Author(s):

Partha M. Das ◽

Rakesh Singal

Keyword(s):

Dna Methylation ◽

Histone Deacetylase Inhibitors ◽

Promoter Regions ◽

Methyl Transferase ◽

Dietary Folate ◽

Small Interference Rna ◽

New Information ◽

Important Regulator ◽

Cancer Tissues ◽

Methylation Patterns

DNA methylation is an important regulator of gene transcription, and its role in carcinogenesis has been a topic of considerable interest in the last few years. Alterations in DNA methylation are common in a variety of tumors as well as in development. Of all epigenetic modifications, hypermethylation, which represses transcription of the promoter regions of tumor suppressor genes leading to gene silencing, has been most extensively studied. However, global hypomethylation has also been recognized as a cause of oncogenesis. New information concerning the mechanism of methylation and its control has led to the discovery of many regulatory proteins and enzymes. The contribution of dietary folate and methylene terahydrofolate reductase polymorphisms to methylation patterns in normal and cancer tissues is under intense investigation. As methylation occurs early and can be detected in body fluids, it may be of potential use in early detection of tumors and for determining the prognosis. Because DNA methylation is reversible, drugs like 5′-azacytidine, decitabine, and histone deacetylase inhibitors are being used to treat a variety of tumors. Novel demethylating agents such as antisense DNA methyl transferase and small interference RNA are being developed, making the field of DNA methylation wider and more exciting.

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Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1270-1278.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1270-1278 ◽

Cited By ~ 141

Author(s):

Jonathan C. Cheng ◽

Daniel J. Weisenberger ◽

Felicidad A. Gonzales ◽

Gangning Liang ◽

Guo-Liang Xu ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Promoter Regions ◽

Bladder Cancer Cells ◽

Continuous Application ◽

Aberrant Dna Methylation ◽

Human Bladder Cancer Cells ◽

Partial Depletion

ABSTRACT During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Recently, we reported that zebularine [1-(β-d-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. Here we show that continuous application of zebularine to T24 cells induces and maintains p16 gene expression and sustains demethylation of the 5′ region for over 40 days, preventing remethylation. In addition, continuous zebularine treatment effectively and globally demethylated various hypermethylated regions, especially CpG-poor regions. The drug caused a complete depletion of extractable DNA methyltransferase 1 (DNMT1) and partial depletion of DNMT3a and DNMT3b3. Last, sequential treatment with 5-aza-2′-deoxycytidine followed by zebularine hindered the remethylation of the p16 5′ region and gene resilencing, suggesting the possible combination use of both drugs as a potential anticancer regimen.

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Profiling of Aberrant DNA Methylation In AML Reveals Subclasses of CpG Islands with Epigenetic or Genetic Association

Blood ◽

10.1182/blood.v116.21.2498.2498 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2498-2498

Author(s):

Claudia Gebhard ◽

Mohammed Sadeh ◽

Dagmar Glatz ◽

Lucia Schwarzfischer ◽

Rainer Spang ◽

...

Keyword(s):

Dna Methylation ◽

De Novo ◽

Conflicts Of Interest ◽

Cpg Island ◽

Cpg Islands ◽

Sequencing Data ◽

Cpg Island Methylator Phenotype ◽

Chip Sequencing ◽

Aberrant Dna Methylation ◽

Methylation Patterns

Abstract Abstract 2498 CpG islands show frequent and often disease-specific epigenetic alterations during malignant transformation, however, the underlying mechanisms are poorly understood. We used methyl-CpG immunoprecipitation (MCIp) to generate comparative DNA methylation profiles of 30 patients with acute myeloid leukemia for human CpG islands across the genome. DNA methylation profiles across 23.000 CpG islands revealed highly heterogeneous methylation patterns in AML with over 6000 CpG islands showing aberrant de novo methylation in AML. Based on these profiles we selected a subset of 380 CpG islands (covering 15.000 individual CpGs) for detailed fine-mapping analyses of aberrant DNA methylation in 185 patients with AML (50% normal karyotype). We found that a proportion of patients (5/185) displayed a concerted hypermethylation at almost all studied loci, representing the rare CpG island methylator phenotype (CIMP) in AML. Meta analysis of methylation profiling and published ChIP sequencing data separated CpG islands in two groups. A highly correlated subgroup of CpG island regions was strongly associated with histone H3 lysine 27 trimethylation in human hematopoietic progenitor cells, suggesting that disease-related de novo DNA methylation at these CpG islands is linked with polycomb group protein (PcG)-mediated repression. The group of mainly non-PcG target CpG islands showed heterogeneous methylation patterns across patients and unsupervised hierarchical clustering revealed a correlation of methylation profiles with genetic disease markers, including oncofusion proteins as well as CEBPA- and NPM1-mutations. Our study suggests that both epigenetic as well as genetic aberrations may underlay AML-related changes in CpG island DNA methylation states. Disclosures: No relevant conflicts of interest to declare.

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