Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer

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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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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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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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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∆ DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis

EBioMedicine ◽

10.1016/j.ebiom.2015.09.002 ◽

2015 ◽

Vol 2 (10) ◽

pp. 1340-1350 ◽

Cited By ~ 3

Author(s):

Mark Z. Ma ◽

Ruxian Lin ◽

José Carrillo ◽

Manisha Bhutani ◽

Ashutosh Pathak ◽

...

Keyword(s):

Dna Methylation ◽

Lung Tumorigenesis ◽

Aberrant Dna Methylation ◽

Methylation Patterns

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The CLASSY family controls tissue-specific DNA methylation patterns in Arabidopsis

Nature Communications ◽

10.1038/s41467-021-27690-x ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Ming Zhou ◽

Ceyda Coruh ◽

Guanghui Xu ◽

Laura M. Martins ◽

Clara Bourbousse ◽

...

Keyword(s):

Dna Methylation ◽

Global Scale ◽

Epigenetic Landscape ◽

Specific Expression ◽

Tissue Specific ◽

Dna Motif ◽

Epigenetic Diversity ◽

Aberrant Dna Methylation ◽

Open Question ◽

Methylation Patterns

AbstractDNA methylation shapes the epigenetic landscape of the genome, plays critical roles in regulating gene expression, and ensures transposon silencing. As is evidenced by the numerous defects associated with aberrant DNA methylation landscapes, establishing proper tissue-specific methylation patterns is critical. Yet, how such differences arise remains a largely open question in both plants and animals. Here we demonstrate that CLASSY1-4 (CLSY1-4), four locus-specific regulators of DNA methylation, also control tissue-specific methylation patterns, with the most striking pattern observed in ovules where CLSY3 and CLSY4 control DNA methylation at loci with a highly conserved DNA motif. On a more global scale, we demonstrate that specific clsy mutants are sufficient to shift the epigenetic landscape between tissues. Together, these findings reveal substantial epigenetic diversity between tissues and assign these changes to specific CLSY proteins, elucidating how locus-specific targeting combined with tissue-specific expression enables the CLSYs to generate epigenetic diversity during plant development.

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Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options

Blood ◽

10.1182/blood-2009-06-227660 ◽

2009 ◽

Vol 114 (27) ◽

pp. 5490-5498 ◽

Cited By ~ 94

Author(s):

Dominique J. P. M. Stumpel ◽

Pauline Schneider ◽

Eddy H. J. van Roon ◽

Judith M. Boer ◽

Paola de Lorenzo ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Acute Lymphoblastic Leukemia ◽

Clinical Outcome ◽

Cpg Island ◽

Lymphoblastic Leukemia ◽

Promoter Hypermethylation ◽

Aberrant Dna Methylation ◽

Methylation Patterns ◽

Infant Acute Lymphoblastic Leukemia

Abstract MLL-rearranged infant acute lymphoblastic leukemia (ALL) remains the most aggressive type of childhood leukemia, displaying a unique gene expression profile. Here we hypothesized that this characteristic gene expression signature may have been established by potentially reversible epigenetic modifications. To test this hypothesis, we used differential methylation hybridization to explore the DNA methylation patterns underlying MLL-rearranged ALL in infants. The obtained results were correlated with gene expression data to confirm gene silencing as a result of promoter hypermethylation. Distinct promoter CpG island methylation patterns separated different genetic subtypes of MLL-rearranged ALL in infants. MLL translocations t(4;11) and t(11;19) characterized extensively hypermethylated leukemias, whereas t(9;11)-positive infant ALL and infant ALL carrying wild-type MLL genes epigenetically resembled normal bone marrow. Furthermore, the degree of promoter hypermethylation among infant ALL patients carrying t(4;11) or t(11;19) appeared to influence relapse-free survival, with patients displaying accentuated methylation being at high relapse risk. Finally, we show that the demethylating agent zebularine reverses aberrant DNA methylation and effectively induces apoptosis in MLL-rearranged ALL cells. Collectively these data suggest that aberrant DNA methylation occurs in the majority of MLL-rearranged infant ALL cases and guides clinical outcome. Therefore, inhibition of aberrant DNA methylation may be an important novel therapeutic strategy for MLL-rearranged ALL in infants.

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