DNA Methylation and Cancer

2004 ◽  
Vol 22 (22) ◽  
pp. 4632-4642 ◽  
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.

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

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4681-4691 ◽  
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.

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

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.

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

2003 ◽  
Vol 81 (3) ◽  
pp. 197-208 ◽  
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.

scholarly journals PCR-Based Methods for Detecting Single-Locus DNA Methylation Biomarkers in Cancer Diagnostics, Prognostics, and Response to Treatment

2009 ◽  
Vol 55 (8) ◽  
pp. 1471-1483 ◽  
Author(s):  
Lasse Sommer Kristensen ◽  
Lise Lotte Hansen
Keyword(s):  
Dna Methylation ◽  
Epigenetic Modification ◽  
Cancer Diagnostics ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Diagnostic Tools ◽  
Promoter Regions ◽  
Advantages And Disadvantages ◽  
Specific Pcr ◽  
Methylation Patterns

Abstract Background: DNA methylation is a highly characterized epigenetic modification of the human genome that is implicated in cancer. The altered DNA methylation patterns found in cancer cells include not only global hypomethylation but also discrete hypermethylation of specific genes. In particular, numerous tumor suppressor genes undergo epigenetic silencing because of hypermethylated promoter regions. Some of these genes are considered promising DNA methylation biomarkers for early cancer diagnostics, and some have been shown to be valuable for predicting prognosis or the response to therapy. Content: PCR-based methods that use sodium bisulfite–treated DNA as a template are generally accepted as the most analytically sensitive and specific techniques for analyzing DNA methylation at single loci. A number of new methods, such as methylation-specific fluorescent amplicon generation (MS-FLAG), methylation-sensitive high-resolution melting (MS-HRM), and sensitive melting analysis after real-time methylation-specific PCR (SMART-MSP), now complement the traditional PCR-based methods and promise to be valuable diagnostic tools. In particular, the HRM technique shows great potential as a diagnostic tool because of its closed-tube format and cost-effectiveness. Summary: Numerous traditional and new PCR-based methods have been developed for detecting DNA methylation at single loci. All have characteristic advantages and disadvantages, particularly with regard to use in clinical settings.

scholarly journals The DNA methylation landscape of five pediatric-tumor types

2021 ◽  
Author(s):  
Alyssa C Parker ◽  
Badí I Quinteros ◽  
Stephen R Piccolo
Keyword(s):  
Dna Methylation ◽  
Pediatric Cancer ◽  
Cancer Type ◽  
Pediatric Tumors ◽  
Promoter Regions ◽  
Pediatric Tumor ◽  
Aberrant Dna Methylation ◽  
Rhabdoid Tumors ◽  
Tumor Types ◽  
Methylation Patterns

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.

scholarly journals A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples

2021 ◽  
Author(s):  
Yasmine Sommerer ◽  
Olena Ohlei ◽  
Valerija Dobricic ◽  
Derek H. Oakley ◽  
Tanja Wesse ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Association Studies ◽  
Promoter Regions ◽  
Functional Interpretation ◽  
Peripheral Tissues ◽  
Cpg Sites ◽  
Dorsolateral Prefrontal ◽  
Significant Enrichment ◽  
Methylation Patterns

Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n=120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (False Discovery Rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.

scholarly journals Decoupling of DNA Methylation Status and Gene Expression Levels in Aging Individuals

2018 ◽  
Vol 4 (2) ◽  
pp. 100040 ◽  
Author(s):  
Anna Wierczeiko ◽  
David Fournier ◽  
Hristo Todorov ◽  
Susanne Klingenberg ◽  
Kristina Endres ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
Age Groups ◽  
Epigenetic Factors ◽  
Promoter Regions ◽  
Methylation Patterns ◽  
The Impact ◽  
Gene Expression Levels

Aging is a multi-factorial process, where epigenetic factors play one of the major roles in declines of gene expression and organic function. DNA methylation at CpG islands of promoters can directly change the expression of the neighbouring gene mostly through inhibition. Furthermore, it is known that DNA methylation patterns change during aging In our study, we investigated gene regulation through DNA methylation of genes up- and downregulated in long-lived people compared to a younger cohort. Our data revealed that comparatively highly methylated genes were associated with high expression in long-lived people (e.g. over 85). Genes with lower levels of methylation were associated with low expression. These findings might contradict the general model used to associate methylation status with expression. Indeed, we found that methylation in the promoter regions of all investigated genes is rather constant across different age groups, meaning that the disparity between methylation and expression only happens in older people. A potential explanation could be the impact of other epigenetic mechanisms, possibly related to stress.

scholarly journals DNA methylation patterns of behavior-related gene promoter regions dissect the gray wolf from domestic dog breeds

2017 ◽  
Vol 292 (3) ◽  
pp. 685-697 ◽  
Author(s):  
Zsofia Banlaki ◽  
Giulia Cimarelli ◽  
Zsofia Viranyi ◽  
Eniko Kubinyi ◽  
Maria Sasvari-Szekely ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Promoter ◽  
Domestic Dog ◽  
Gray Wolf ◽  
Related Gene ◽  
Promoter Regions ◽  
Patterns Of Behavior ◽  
Methylation Patterns

Sex-biased DNA methylation in papillary thyroid cancer

2021 ◽  
Vol 15 (2) ◽  
pp. 109-120
Author(s):  
Rui Han ◽  
Wei Sun ◽  
Jiapeng Huang ◽  
Liang Shao ◽  
Hao Zhang
Keyword(s):  
Dna Methylation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Immune Cell ◽  
Gene Promoter ◽  
Papillary Thyroid ◽  
Promoter Regions ◽  
Genomic Regions ◽  
Methylation Patterns ◽  
The Relationship

Background: Women have a higher risk of developing papillary thyroid cancer (PTC) than men. DNA methylation is known to differ between men and women. Materials & methods: Using the human methylation 450 BeadChip and RNA-sequence, we profiled the genome-wide DNA methylation patterns of papillary thyroid carcinoma patients and para-carcinoma tissue. Results: We first identified 398 different expression genes (DEGs) between males and females PTC. Then we analyzed the relationship between differentially methylated positions (DMPs) and DEGs at gene promoter regions and identified 39 genes and explored DMP-DEGs’ correlation with immune cell infiltration and tumor purity. We also analyzed the relationship between genomic regions and enhancers. Conclusion: Our study identified 39 DMP-DEGs providing some new insights into the mechanisms of methylation-mediated gender differences in PTC.

Examination of the dynamics of global DNA methylation pattern establishment during spermatogenesiss

2007 ◽  
Vol 30 (4) ◽  
pp. 90
Author(s):  
Kirsten Niles ◽  
Sophie La Salle ◽  
Christopher Oakes ◽  
Jacquetta Trasler
Keyword(s):  
Dna Methylation ◽  
Germ Cell ◽  
Germ Cells ◽  
Epigenetic Modification ◽  
Methylation Pattern ◽  
Chromosome 9 ◽  
Specific Gene ◽  
Global Methylation ◽  
Dna Methylation Pattern ◽  
Methylation Patterns

Background: DNA methylation is an epigenetic modification involved in gene expression, genome stability, and genomic imprinting. In the male, methylation patterns are initially erased in primordial germ cells (PGCs) as they enter the gonadal ridge; methylation patterns are then acquired on CpG dinucleotides during gametogenesis. Correct pattern establishment is essential for normal spermatogenesis. To date, the characterization and timing of methylation pattern acquisition in PGCs has been described using a limited number of specific gene loci. This study aimed to describe DNA methylation pattern establishment dynamics during male gametogenesis through global methylation profiling techniques in a mouse model. Methods: Using a chromosome based approach, primers were designed for 24 regions spanning chromosome 9; intergenic, non-repeat, non-CpG island sequences were chosen for study based on previous evidence that these types of sequences are targets for testis-specific methylation events. The percent methylation was determined in each region by quantitative analysis of DNA methylation using real-time PCR (qAMP). The germ cell-specific pattern was determined by comparing methylation between spermatozoa and liver. To examine methylation in developing germ cells, spermatogonia from 2 day- and 6 day-old Oct4-GFP (green fluorescent protein) mice were isolated using fluorescence activated cell sorting. Results: As compared to liver, four loci were hypomethylated and five loci were hypermethylated in spermatozoa, supporting previous results indicating a unique methylation pattern in male germ cells. Only one region was hypomethylated and no regions were hypermethylated in day 6 spermatogonia as compared to mature spermatozoa, signifying that the bulk of DNA methylation is established prior to type A spermatogonia. The methylation in day 2 spermatogonia, germ cells that are just commencing mitosis, revealed differences of 15-20% compared to day 6 spermatogonia at five regions indicating that the most crucial phase of DNA methylation acquisition occurs prenatally. Conclusion: Together, these studies provide further evidence that germ cell methylation patterns differ from those in somatic tissues and suggest that much of methylation at intergenic sites is acquired during prenatal germ cell development. (Supported by CIHR)

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