Aim: The aim of the study was to evaluate the use of global and gene-specific DNA methylation changes as potential biomarkers for gallbladder cancer (GBC) in a cohort from Chile. Material & methods: DNA methylation was analyzed through an ELISA-based technique and quantitative methylation-specific PCR. Results: Global DNA Methylation Index (p = 0.02) and promoter methylation of SSBP2 (p = 0.01) and ESR1 (p = 0.05) were significantly different in GBC when compared with cholecystitis. Receiver curve operator analysis revealed promoter methylation of APC, CDKN2A, ESR1, PGP9.5 and SSBP2, together with the Global DNA Methylation Index, had 71% sensitivity, 95% specificity, a 0.97 area under the curve and a positive predictive value of 90%. Conclusion: Global and gene-specific DNA methylation may be useful biomarkers for GBC clinical assessment ...
Background/Purpose: Cutaneous lupus erythematous (CLE) is a disfiguring manifestation of systemic LE (SLE), and the pathogenesis remains unclear. However, epidermal regulation of skin inflammation and cell death contribute, potentially in a female-biased manner. Differential DNA methylation is important in the organ-specific manifestations of SLE but has not been studied in the skin. Thus, we explored the genome-wide DNA methylation changes in keratinocytes (KC) to investigate the functional relevance in CLE.. Methods: Eight SLE skin biopsy samples were taken from non-sun-exposed, unaffected skin from participants of the Michigan Lupus Cohort as well as age (+/- 6 years), sex, and ethnicity-matched healthy control subjects. Freshly cultured KC (at passage 2) were used to isolate DNA using DNeasy Blood and Tissue Kit. DNA was bisulfite converted for DNA methylation studies using the EZ DNA Methylation Kit. Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 ...
TY - JOUR. T1 - Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia. AU - Pei, Lirong. AU - Choi, Jeong-Hyeon. AU - Liu, Jimei. AU - Lee, Eun Joon. AU - McCarthy, Brian. AU - Wilson, James M.. AU - Speir, Ethan. AU - Awan, Farrukh. AU - Tae, Hongseok. AU - Arthur, Gerald. AU - Schnabel, Jennifer L.. AU - Taylor, Kristen H.. AU - Wang, Xinguo. AU - Xu, Dong. AU - Ding, Hanfei. AU - Munn, David H. AU - Caldwell, Charles W.. AU - Shi, Huidong. PY - 2012/6. Y1 - 2012/6. N2 - We conducted a genome-wide DNA methylation analysis in CD19+ B-cells from chronic lymphocytic leukemia (CLL) patients and normal control samples using reduced representation bisulfite sequencing (RRBS). The methylation status of 1.8-2.3 million CpGs in the CLL genome was determined; about 45% of these CpGs were located in more than 23,000 CpG islands (CGIs). While global CpG methylation was similar between CLL and normal B-cells, 1,764 gene promoters were identified as being ...
Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation cityscape plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and ...
TY - CHAP. T1 - Computational Approaches in Next-Generation Sequencing Data Analysis for Genome-Wide DNA Methylation Studies. AU - Choi, Jeong Hyeon. AU - Shi, Huidong. PY - 2016/9/6. Y1 - 2016/9/6. N2 - DNA methylation is one of the most important epigenetic mechanisms that ensures the maintenance and inheritance of gene-expression programs in mammalian cells. Three highly conserved DNA methyltransferase (DNMT) proteins (DNMT1, DNMT3A, and DNMT3B), which complex together in vivo, establish and maintain the DNA methylation landscape within the human genome. These novel next-generation sequencing (NGS) platforms also have many other advantages over the current platforms such as less bias during template preparation, possible longer read length, lower cost, higher speed, and better accuracy. The chapter presents the enrichment-based sequencing and bisulfite treatment-based approaches have successfully profiled DNA methylation and identified genome-wide differential methylation. The DMRs are ...
Cancer Epigenetics: An Introduction -- Community Resources and Technologies Developed Through the NIH Roadmap Epigenomics Program -- Epigenome-Wide Association Studies (EWAS): Past, Present, and Future -- Epigenetic Biomarkers in Liver Cancer -- Cancer Type Specific Epigenetic Changes: Gastric Cancer -- Beyond the Island: Epigenetic Biomarkers of Colorectal and Prostate Cancer -- Prostate Cancer Epigenome -- CpG Island Hypermethylation as a Biomarker for the Early Detection of Lung Cancer -- Analysis of DNA Methylation in Pancreatic Cancer: An Update -- Epigenetics of Urothelial Carcinoma -- Epigenetics of Prostate Cancer -- Methylation Profile Landscape in Mesothelioma: Possible Implications in Early Detection, Disease Progression, and Therapeutic Options -- Techniques to Access Histone Modifications and Variants in Cancer -- Single Base Resolution Analysis of 5-Methylcytosine and 5-Hydroxymethylcytosine by RRBS and TAB-RRBS -- Quantitative DNA Methylation Analysis for Epigenotyping of ...
TY - JOUR. T1 - Quantitative DNA methylation analysis detects cervical intraepithelial neoplasms type 3 and worse. AU - Lai, Hung Cheng. AU - Lin, Ya Wen. AU - Huang, Rui Lan. AU - Chung, Ming Tzeung. AU - Wang, Hui Chen. AU - Liao, Yu Ping. AU - Su, Po Hsuan. AU - Liu, Yung Liang. AU - Yu, Mu Hsien. PY - 2010/9/15. Y1 - 2010/9/15. N2 - BACKGROUND: DNA methylation may be used a potential biomarker for detecting cervical cancer. The authors of this report used quantitative methylation analysis of 4 genes in a full spectrum of cervical lesions to test its potential clinical application. METHODS: This hospital-based, retrospective, case-control study was conducted in 185 patients and included patients who had a normal uterine cervix (n = 53), cervical intraepithelial neoplasm type 1 (CIN1) (n = 37), CIN2 (n = 22), CIN3 (n = 24), carcinoma in situ (CIS) (n = 22), squamous cell carcinoma (SCC, n = 20), and adenocarcinoma (AC) (n = 7). Methylation levels of the genes sex-determining region Y, box 1 ...
Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies. To this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects. We found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed
TY - JOUR. T1 - Association of DNA methylation differences with schizophrenia in an epigenome-wide association study. AU - Montano, Carolina. AU - Taub, Margaret Anne. AU - Jaffe, Andrew. AU - Briem, Eirikur. AU - Feinberg, Jason I.. AU - Trygvadottir, Rakel. AU - Idrizi, Adrian. AU - Runarsson, Arni. AU - Berndsen, Birna. AU - Gur, Ruben C.. AU - Moore, Tyler M.. AU - Perry, Rodney T.. AU - Fugman, Doug. AU - Sabunciyan, Sarven. AU - Yolken, Robert H. AU - Hyde, Thomas. AU - Kleinman, Joel. AU - Sobell, Janet L.. AU - Pato, Carlos N.. AU - Pato, Michele T.. AU - Go, Rodney C.. AU - Nimgaonkar, Vishwajit. AU - Weinberger, Daniel. AU - Braff, David. AU - Gur, Raquel E.. AU - Fallin, Daniele Daniele. AU - Feinberg, Andrew P. PY - 2016/5/1. Y1 - 2016/5/1. N2 - Importance: DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. O. Objective: To scan genome-wide DNA methylation data to identify differentially ...
TY - JOUR. T1 - Differences in Genome-wide DNA Methylation Profiles in Breast Milk by Race and Lactation Duration. AU - Davis Lynn, Brittny C.. AU - Bodelon, Clara. AU - Pfeiffer, Ruth M.. AU - Yang, Hannah P.. AU - Yang, Howard H.. AU - Lee, Maxwell. AU - Laird, Peter W.. AU - Campan, Mihaela. AU - Weisenberger, Daniel J.. AU - Murphy, Jeanne. AU - Sampson, Joshua N.. AU - Browne, Eva P.. AU - Anderton, Douglas L.. AU - Sherman, Mark E.. AU - Arcaro, Kathleen F.. AU - Gierach, Gretchen L.. PY - 2019. Y1 - 2019. N2 - Black women in the United States are disproportionately affected by early-onset, triple-negative breast cancer. DNA methylation has shown differences by race in healthy and tumor breast tissues. We examined associations between genome-wide DNA methylation levels in breast milk and breast cancer risk factors, including race, to explain how this reproductive stage influences a womans risk for, and potentially contributes to racial disparities in, breast cancer. Breast milk samples ...
TY - JOUR. T1 - Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer. AU - Banno, Kouji. AU - Yanokura, Megumi. AU - Susumu, Nobuyuki. AU - Kawaguchi, Makiko. AU - Hirao, Nobumaru. AU - Hirasawa, Akira. AU - Tsukazaki, Katsumi. AU - Aoki, Daisuke. PY - 2006/12/1. Y1 - 2006/12/1. N2 - Epigenetic abnormalities including the aberrant DNA hypermethylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis. To identify the genes associated with aberrant DNA hypermethylation in endometrial carcinogenesis, we studied the hypermethylation of the promoter regions of five genes: hMLH1, APC, E-cadherin, RAR-β and p16. The frequencies of aberrant hypermethylation were 40.4% (21/52) in hMLH1, 22% (11/50) in APC, 14% (7/50) in E- cadherin, and 2.3% (1/44) in RAR-β in endometrial cancer specimens. No aberrant DNA methylation was found in p16. In atypical endometrial hyperplasia, the ...
Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). Main Outcome Measures: DFS and OS. Results: In the training cohort, mean methylation of 4
Panic disorder (PD) is considered to be a multifactorial disorder emerging from interactions among multiple genetic and environmental factors. To date, although genetic studies reported several susceptibility genes with PD, few of them were replicated and the pathogenesis of PD remains to be clarified. Epigenetics is considered to play an important role in etiology of complex traits and diseases, and DNA methylation is one of the major forms of epigenetic modifications. In this study, we performed an epigenome-wide association study of PD using DNA methylation arrays so as to investigate the possibility that different levels of DNA methylation might be associated with PD. The DNA methylation levels of CpG sites across the genome were examined with genomic DNA samples (PD, N = 48, control, N = 48) extracted from peripheral blood. Methylation arrays were used for the analysis. β values, which represent the levels of DNA methylation, were normalized via an appropriate pipeline. Then, β values were
TY - JOUR. T1 - Minimal evidence for consistent changes in maize DNA methylation patterns following environmental stress. AU - Eichten, Steven R.. AU - Springer, Nathan M.. PY - 2015/5/30. Y1 - 2015/5/30. N2 - DNA methylation is a chromatin modification that is sometimes associated with epigenetic regulation of gene expression. As DNA methylation can be reversible at some loci, it is possible that methylation patterns may change within an organism that is subjected to environmental stress. In order to assess the effects of abiotic stress on DNA methylation patterns in maize (Zea mays), seeding plants were subjected to heat, cold, and UV stress treatments. Tissue was later collected from individual adult plants that had been subjected to stress or control treatments and used to perform DNA methylation profiling to determine whether there were consistent changes in DNA methylation triggered by specific stress treatments. DNA methylation profiling was performed by immunoprecipitation of methylated ...
There is growing interest in the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in brain disorders characterized by mitochondrial dysfunction. However, to date a genome-wide, high-resolution analysis of the mitochondrial DNA methylome has yet to be undertaken. We have used a novel approach to interrogate the mitochondrial DNA methylome at single base resolution using targeted bisulfite sequencing. We applied this method to investigate mitochondrial DNA methylation patterns in post-mortem superior temporal gyrus and cerebellum brain tissue from seven human donors. Here you can explore mitochondria DNA methylation levels in superior temporal gyrus and cerebellum tissue along UCSC tracks. Mitochondrial DNA methylation patterns are relatively low but conserved, with peaks in DNA methylation ,5% at a number of sites, such as within the D-LOOP and MT-ND5 and higher levels of methylation at non-CpG compared to CpG sites.. ...
Lung cancer is the leading cause of cancer death in men and women in the United States and Western Europe. Over 160,000 Americans die of this disease every year. The five-year survival rate is 15% - significantly lower than that of other major cancers. Early detection is a key factor in increasing lung cancer patient survival. DNA hypermethylation is recognized as an important mechanism for tumor suppressor gene inactivation in cancer and could yield powerful biomarkers for early detection of lung cancer. Here we focused on developing DNA methylation markers for squamous cell carcinoma of the lung. Using the sensitive, high-throughput DNA methylation analysis technique MethyLight, we examined the methylation profile of 42 loci in a collection of 45 squamous cell lung cancer samples and adjacent non-tumor lung tissues from the same patients. We identified 22 loci showing significantly higher DNA methylation levels in tumor tissue than adjacent non-tumor lung. Of these, eight showed highly significant
TY - JOUR. T1 - Regulation and function of DNA methylation in plants and animals. AU - He, Xinjian. AU - Chen, Taiping. AU - Zhu, Jian-Kang. N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: This work was supported by the National Institutes of Health grants R01GM070795 and R01GM059138 to J-KZ.. PY - 2011/2/15. Y1 - 2011/2/15. N2 - DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt ...
Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study, we have combined laser-capture microdissection with reduced representation bisulfite sequencing to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology analysis demonstrated that DMRs associated with promoters
Cardiac disease modelling using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) requires thorough insight into cardiac cell type differentiation processes. However, current methods to discriminate different cardiac cell types are mostly time-consuming, are costly and often provide imprecise phenotypic evaluation. DNA methylation plays a critical role during early heart development and cardiac cellular specification. We therefore investigated the DNA methylation pattern in different cardiac tissues to identify CpG loci for further cardiac cell type characterization. An array-based genome-wide DNA methylation analysis using Illumina Infinium HumanMethylation450 BeadChips led to the identification of 168 differentially methylated CpG loci in atrial and ventricular human heart tissue samples (n = 49) from different patients with congenital heart defects (CHD). Systematic evaluation of atrial-ventricular DNA methylation pattern in cardiac tissues in an independent sample cohort of non
Foret, S; Kucharski, R; Pellegrini, M; Feng, S; Jacobsen, SE; Robinson, GE and Maleszka, R (2012) DNA methylation dynamics, metabolic fluxes, gene splicing, and alternative phenotypes in honey bees. Proceedings of the National Academy of Sciences of the United States of America. 109(13): 4968-4973 ...
Prostate cancer (PC) is the most commonly diagnosed neoplasm and the third most common cause of cancer-related death amongst men in the Western world. PC is a clinically highly heterogeneous disease, and distinction between aggressive and indolent disease is a major challenge for the management of PC. Currently, no biomarkers or prognostic tools are able to accurately predict tumor progression at the time of diagnosis. Thus, improved biomarkers for PC prognosis are urgently needed. This review focuses on the prognostic potential of DNA methylation biomarkers for PC. Epigenetic changes are hallmarks of PC and associated with malignant initiation as well as tumor progression. Moreover, DNA methylation is the most frequently studied epigenetic alteration in PC, and the prognostic potential of DNA methylation markers for PC has been demonstrated in multiple studies. The most promising methylation marker candidates identified so far include PITX2, C1orf114 (CCDC181) and the GABRE~miR-452~miR-224 ...
TY - JOUR. T1 - Diagnostic markers of urothelial cancer based on DNA methylation analysis. AU - Chihara, Yoshitomo. AU - Kanai, Yae. AU - Fujimoto, Hiroyuki. AU - Sugano, Kokichi. AU - Kawashima, Kiyotaka. AU - Liang, Gangning. AU - Jones, Peter A.. AU - Fujimoto, Kiyohide. AU - Kuniyasu, Hiroki. AU - Hirao, Yoshihiko. PY - 2013. Y1 - 2013. N2 - BACKGROUND: Early detection and risk assessment are crucial for treating urothelial cancer (UC), which is characterized by a high recurrence rate, and necessitates frequent and invasive monitoring. We aimed to establish diagnostic markers for UC based on DNA methylation.METHODS: In this multi-center study, three independent sample sets were prepared. First, DNA methylation levels at CpG loci were measured in the training sets (tumor samples from 91 UC patients, corresponding normal-appearing tissue from these patients, and 12 normal tissues from age-matched bladder cancer-free patients) using the Illumina Golden Gate methylation assay to identify ...
Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes. For example, the DNMT3L/DNMT3A complex is mainly related to de novo DNA methylation in embryonic states, whereas the DNMT1/PCNA/UHRF1 complex is required for maintaining global DNA methylation following DNA replication. On the opposite to these unspecific DNA methylation machineries (no preferential DNA sequence), some recently identified DNMT-including complexes are recruited on specific DNA sequences. The coexistence of both types of DNA methylation (un
Type 2 diabetes mellitus (T2D) is a slowly progressive disease that can be postponed or even avoided through lifestyle changes. Recent data demonstrate highly significant correlations between DNA methylation and the most important risk factors of T2D, including age and BMI, in blood and human tissues relevant to insulin resistance and T2D. Also, T2D patients and individuals with increased risk of the disease display differential DNA methylation profiles and plasticity compared to controls. Accordingly, the novel clues to DNA methylation fingerprints in blood and tissues with deteriorated metabolic capacity indicate that blood-borne epigenetic biomarkers of T2D progression might become a reality. This Mini Review will address the most recent associations between DNA methylation and diabetes-related traits in human tissues and blood. The overall focus is on the potential of future epigenome-wide studies, carried out across tissues and populations with correlations to pre-diabetes and T2D risk factors, to
TY - JOUR. T1 - Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimers disease. AU - Konki, Mikko. AU - Malonzo, Maia. AU - K Karlsson, Ida. AU - Lindgren, Noora. AU - Ghimire, Bishwa. AU - Smolander, Johannes. AU - M Scheinin, Noora. AU - Ollikainen, Miina. AU - Laiho, Asta. AU - L Elo, Laura. AU - Lönnberg, Tapio. AU - Röyttä, Matias. AU - Pedersen, Nancy L.. AU - Kaprio, Jaakko. AU - Lähdesmäki, Harri. AU - O Rinne, Juha. AU - J Lund, Riikka. PY - 2019. Y1 - 2019. N2 - Background Alzheimers disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized ...
Maintaining and acquiring the pluripotent cell state in plants is critical to tissue regeneration and vegetative multiplication. Histone-based epigenetic mechanisms are important for regulating this undifferentiated state. Here we report the use of genetic and pharmacological experimental approaches to show that Arabidopsis cell suspensions and calluses specifically repress some genes as a result of promoter DNA hypermethylation. We found that promoters of the MAPK12, GSTU10 and BXL1 genes become hypermethylated in callus cells and that hypermethylation also affects the TTG1, GSTF5, SUVH8, fimbrin and CCD7 genes in cell suspensions. Promoter hypermethylation in undifferentiated cells was associated with histone hypoacetylation and primarily occurred at CpG sites. Accordingly, we found that the process specifically depends on MET1 and DRM2 methyltransferases, as demonstrated with DNA methyltransferase mutants. Our results suggest that promoter DNA methylation may be another important epigenetic ...
The incidence of cervical adenocarcinoma (CA) is rising, whereas the incidence of cervical squamous cell carcinoma (CSCC) continues to decrease. However, it is still unclear whether different molecular characteristics underlie these 2 types of cervical carcinoma. To better understand the epigenetic characteristics of cervical carcinoma, we investigated the DNA promoter hypermethylation profiles in CA and CSCC. In addition, we investigated whether DNA hypermethylation patterns might be used for the molecular diagnosis of CA and endometrial adenocarcinoma (EA). Using the bisulfite-modification technique and methylation-specific PCR, we examined the aberrant promoter hypermethylation patterns of 9 tumor suppressor genes (APC, DAPK, CDH1, HLTF, hMLH1, p16, RASSF1A, THBS1 and TIMP3) in 62 CSCCs, 30 CAs and 21 EAs. After Bonferroni correction adjustment (statistically significant at p , 0.0055), we found that the aberrant hypermethylations of CDH1 and DAPK were more frequent in CSCCs than in CAs ...
Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the ...
It is widely known that maternal physical exercise is able to induce beneficial improvements in offspring cognition; however, the effects of paternal exercise have not been explored in detail. The present study was designed to evaluate the impact of paternal physical exercise on memory and learning, neuroplasticity and DNA methylation levels in the hippocampus of male offspring. Adult male Wistar rats were divided into two groups: sedentary or exercised fathers. The paternal preconception exercise protocol consisted of treadmill running, 20 minutes daily, 5 consecutive days per week for 22 days, while the mothers were not trained. After mating, paternal sperm was collected for global DNA methylation analysis. At postnatal day 53, the offspring were euthanized, and the hippocampus was dissected to measure cell survival by 5-bromo-2′-deoxiuridine and to determine the expression of synaptophysin, reelin, brain-derived neurotrophic factor and global DNA methylation levels. To measure spatial ...
Genome-wide hypomethylation is a hallmark of many cancers and is thought to contribute to tumorigenesis independently of CpG island hypermethylation ( 9, 33, 37). Expanding on early observations from a very limited number of gliomas ( 5, 38), we found that genomic hypomethylation occurs at a high frequency in GBM and GBM cell lines. Interestingly, global hypomethylation was not observed in two primary GBMs, indicating that a small proportion of GBMs may arise in the absence of extensive demethylation, although these two tumors exhibit clear differences in genetic and proliferative characteristics relative to severely hypomethylated tumors. However, the whole-genome approach to quantify DNA methylation is not sufficiently sensitive to detect potentially important regional reductions in 5-methylcytosine that can contribute to genomic instability. The high prevalence of genomic hypomethylation in GBM supports an important role for 5-methylcytosine reduction in GBM pathology.. Global decreases in ...
TY - JOUR. T1 - Comparison of different normalization assumptions for analyses of DNA methylation data from the cancer genome. AU - Wang, Dong. AU - Zhang, Yuannv. AU - Huang, Yan. AU - Li, Pengfei. AU - Wang, Mingyue. AU - Wu, Ruihong. AU - Cheng, Lixin. AU - Zhang, Wenjing. AU - Zhang, Yujing. AU - Li, Bin. AU - Wang, Chenguang. AU - Guo, Zheng. PY - 2012/9/10. Y1 - 2012/9/10. N2 - Nowadays, some researchers normalized DNA methylation arrays data in order to remove the technical artifacts introduced by experimental differences in sample preparation, array processing and other factors. However, other researchers analyzed DNA methylation arrays without performing data normalization considering that current normalizations for methylation data may distort real differences between normal and cancer samples because cancer genomes may be extensively subject to hypomethylation and the total amount of CpG methylation might differ substantially among samples. In this study, using eight datasets by ...
To demonstrate the presence of CpG island methylation in these 27 up-regulated miRNAs, we undertook bisulfite genomic sequencing analyses of multiple clones in the metastatic cancer cell from which the miRNA expression microarray data were obtained. We found dense CpG island hypermethylation in 16 (59%) of the described miRNAs (Fig. 1A and Table S2). We wanted to focus on the cancer-specific DNA methylation changes, so we used bisulfite genomic sequencing to analyze the DNA methylation status of these 16 miRNAs in normal tissues (n = 32), including colorectal mucosa, lymphocytes, and skin, to exclude tissue-specific DNA methylation patterns. The expression of many miRNAs is tightly regulated according to cell type (1, 2), so it was not surprising to observe that 11 (65%) of the miRNAs were also densely methylated in normal tissues (Fig. 1A, Table S2, and Fig. S1). The previously mentioned miR-126 was one of these. However, and most importantly, miR148a, miR-34b/c, miR-9-1, miR-9-2, and miR-9-3 ...
TY - JOUR. T1 - Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohns Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci. AU - Adams, Alex T. AU - Kennedy, Nicholas A. AU - Hansen, Richard. AU - Ventham, Nicholas T. AU - OʼLeary, Kate R. AU - Drummond, Hazel E. AU - Noble, Colin L. AU - El-Omar, Emad. AU - Russell, Richard K. AU - Wilson, David C. AU - Nimmo, Elaine R. AU - Hold, Georgina L. AU - Satsangi, Jack. PY - 2014/10. Y1 - 2014/10. N2 - BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohns disease (CD) and is especially pertinent to early onset disease.METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. ...
Abnormal DNA methylation patterns have been demonstrated to be associated with the pathogenesis of Alzheimers disease (AD). The present study aimed to identify differential methylation in the superior temporal gyrus (STG) of patients with late‑onset AD based on epigenome‑wide DNA methylation data by bioinformatics analysis. The genome‑wide DNA methylation data in the STG region of 34 patients with late‑onset AD and 34 controls without dementia were recruited from the Gene Expression Omnibus database. Through systemic quality control, differentially methylated CpG sites were determined by the Students t‑test and mean methylation value differences between the two conditions. Hierarchical clustering analysis was applied to assess the classification performance of differentially methylated CpGs. Functional analysis was performed to investigate the biological functions of the genes associated with differentially methylated CpGs. A total of 17,895 differentially methylated CpG sites were ...
The potential influence of underlying differences in relative leukocyte distributions in studies involving blood-based profiling of DNA methylation is well recognized and has prompted development of a set of statistical methods for inferring changes in the distribution of white blood cells using DNA methylation signatures. However, the extent to which this methodology can accurately predict cell type proportions based on blood-derived DNA methylation data in a large-scale epigenome-wide association study (EWAS) has yet to be examined. We used publicly available data deposited in the Gene Expression Omnibus (GEO) database (accession no. GSE37008), which consisted of both blood-derived epigenome-wide DNA methylation data assayed using the Illumina Infinium HumanMethylation27 BeadArray and complete blood cell (CBC) counts among a community cohort of 94 non-diseased individuals. Constrained projection (CP) was used to obtain predictions of the proportions of lymphocytes, monocytes, and granulocytes ...
DNA methylation (global and gene-specific) has been reported as an epigenetic mechanism that could be involved in the pathogenesis of type 2 diabetes mellitus (T2DM). Furthermore, epigenetic therapy has been suggested as a future possibility for T2DM treatment. Epigenetic changes illustrate the environmental link of the disease. Since some of the epigenetic modifications can be reversed, they could be used as potential therapeutic targets. The aim of the systematic review will be to synthesise the available evidence pertaining to the link between DNA methylation and T2DM. The systematic review will evaluate characteristics of reported studies such as the source of DNA used, methods of quantifying DNA methylation and the participants demographics (age, gender, race and adiposity). We will conduct a narrative synthesis of data, and if there are an adequate number of sufficiently homogenous studies, we will consider performing a meta-analysis. The review will evaluate if the levels of DNA methylation are
BACKGROUND: The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome. METHODS: We investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing. RESULTS: At a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental ...
DNA methylation-based biomarkers were suggested to be promising for early cancer diagnosis. However, DNA methylation-based biomarkers for esophageal squamous cell carcinoma (ESCC), especially in Chinese Han populations have not been identified and evaluated quantitatively. To identify the candidate DNA-methylation based biomarkers for ESCC diagnosis, we performed the targeted bisulfite sequencing analysis in this study. Based on these 94 pairs of ESCC tumors and adjacent normal tissues, we found out that ADHFE1, EOMES, SALL1 and TFPI2 could be an effective methylation-based assay for ESCC diagnosis. ...
BackgroundRenal cell carcinoma (RCC) is the tenth most commonly diagnosed cancer in the United States. While it is usually lethal when metastatic, RCC is successfully treated with surgery when tumors are confined to the kidney and have low tumor volume. Because most early stage renal tumors do not result in symptoms, there is a strong need for biomarkers that can be used to detect the presence of the cancer as well as to monitor patients during and after therapy.MethodsWe examined genome-wide DNA methylation alterations in renal cell carcinomas of diverse histologies and benign adjacent kidney tissues from 96 patients.ResultsWe observed widespread methylation differences between tumors and benign adjacent tissues, particularly in immune-, G-protein coupled receptor-, and metabolism-related genes. Additionally, we identified a single panel of DNA methylation biomarkers that reliably distinguishes tumor from benign adjacent tissue in all of the most common kidney cancer histologic subtypes, and a ...
In recent years several methods have been developed to provide a genome-wide picture of the state of DNA methylation, including: next-generation genome-wide sequencing of bisulfite-converted DNA [8]; methylated DNA immunoprecipitation (MeDIP) followed by either hybridization to high-density oligonucleotide arrays [84] or next-generation sequencing [85]; and dedicated Illumina 27 K and 450 K arrays [86] that measure the state of methylation of well characterized CG sites distributed in the genome. Although genome-wide sequencing is still prohibitively costly for large population studies, array approaches are being frequently used to delineate DNA methylation signatures of disease states in primary clinical material rather than cell lines. Several studies have used this approach to differentiate breast cancer subtypes and their prognosis. Li et al. [87] used 27 K arrays in a small sample of ER/PR+ and ER/PR- breast cancer samples, and identified and validated four genes whose DNA methylation was ...
Perturbation of DNA methylation is frequent in cancers and has emerged as an important mechanism involved in tumorigenesis. To determine how DNA methylation is modified in the genome of primary glioma, we used Methyl-DNA immunoprecipitation (MeDIP) and Nimblegen CpG promoter microarrays to identify differentially DNA methylation sequences between primary glioma and normal brain tissue samples. MeDIP-chip technology was used to investigate the whole-genome differential methylation patterns in glioma and normal brain tissues. Subsequently, the promoter methylation status of eight candidate genes was validated in 40 glioma samples and 4 cell lines by Sequenoms MassARRAY system. Then, the epigenetically regulated expression of these genes and the potential mechanisms were examined by chromatin immunoprecipitation and quantitative real-time PCR. A total of 524 hypermethylated and 104 hypomethylated regions were identified in glioma. Among them, 216 hypermethylated and 60 hypomethylated regions were mapped
1. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, et al. (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20: 332-340. doi: 10.1101/gr.096826.109 20107151. 2. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, et al. (2010) Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 20: 440-446. doi: 10.1101/gr.103606.109 20219944. 3. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, et al. (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20: 434-439. doi: 10.1101/gr.103101.109 20219945. 4. Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, et al. (2012) Distinct DNA methylomes of newborns and centenarians. Proceedings of the National Academy of Sciences.. 5. Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, et al. (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49: 359-67. doi: ...
TY - CHAP. T1 - DNA Methylation Alterations in Human Cancers. AU - Kanai, Yae. AU - Arai, Eri. PY - 2012. Y1 - 2012. UR - http://www.scopus.com/inward/record.url?scp=84882534159&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=84882534159&partnerID=8YFLogxK. U2 - 10.1016/B978-0-12-388415-2.00003-2. DO - 10.1016/B978-0-12-388415-2.00003-2. M3 - Chapter. AN - SCOPUS:84882534159. SN - 9780123884152. SP - 29. EP - 52. BT - Epigenetics in Human Disease. PB - Elsevier Inc.. ER - ...
View more ,Stunting in children is a global public health concern. We investigated how global DNA methylation relates to food intakes, dietary diversity, and development of stunting among 324 children aged 24-36 months in a slum community in Dhaka, Bangladesh. Stunted children (height-for-age z score ˂-2; n = 162) and their age- and sex-matched nonstunted counterparts (height-for-age z score ˃-1; n = 162) were selected by active community surveillance. We studied global DNA methylation, measured as 5-mC% content in whole blood. Dietary intake, anthropometric measurement, and sociodemographic information were obtained. In the multiple linear regression model, increased global DNA methylation level in children was significantly associated with consumption of lower amount of energy, coef: .034 (95% CI [.014, .053]); P = .001, protein, coef: .038 (95% CI [.019, .057]); P = .000, carbohydrate, coef: .027 (95% CI [.008, .047]); P = .006, zinc, coef: .020 (95% CI [.001, .039]); P = .043, total ...
immune Uncategorized IL12RB1, Tropanserin Although aberrant DNA methylation patterning is normally a hallmark of cancer the relevance of targeting DNA methyltransferases (DNMT) remains unclear for some Tropanserin tumors. chemosensitization and demethylation delineating a personalized technique for the clinical usage of DNMTIs. Tropanserin in non-Hodgkin lymphomas (NHL)(2) a meeting associated with even more intense variants of the condition(3). Inactivation of tumor suppressor pathways can be an essential contributor to level of resistance to chemotherapy in cancers(4-6) partly as the activity of all chemotherapy realtors depends to an excellent extent on a single pro-apoptotic and pro-differentiation pathways that are impaired during carcinogenesis. Inactivation of the pathways by Tropanserin mutations or hypermethylation can as a result affect drug awareness(4 7 Gene particular and genomic modifications in DNA methylation have already been described in the many subtypes of NHL(8-14). ...
DNA methylation plays crucial roles in most eukaryotic organisms. Bisulfite sequencing (BS-Seq) is a sequencing approach that provides quantitative cytosine methylation levels in genome-wide scope and single-base resolution. However, genomic variations such as insertions and deletions (indels) affect methylation calling, and the alignment of reads near/across indels becomes inaccurate in the presence of polymorphisms. Hence, the simultaneous detection of DNA methylation and indels is important for exploring the mechanisms of functional regulation in organisms. These problems motivated us to develop the algorithm BatMeth2, which can align BS reads with high accuracy while allowing for variable-length indels with respect to the reference genome. The results from simulated and real bisulfite DNA methylation data demonstrated that our proposed method increases alignment accuracy. Additionally, BatMeth2 can calculate the methylation levels of individual loci, genomic regions or functional regions such as
DNA methylation is an epigenetic mark with important regulatory roles in cellular identity and can be quantified at base resolution using bisulfite sequencing. Most studies are limited to the average DNA methylation levels of individual CpGs and thus neglect heterogeneity within the profiled cell populations. To assess this within-sample heterogeneity (WSH) several window-based scores that quantify variability in DNA methylation in sequencing reads have been proposed. We performed the first systematic comparison of four published WSH scores based on simulated and publicly available datasets. Moreover, we propose two new scores and provide guidelines for selecting appropriate scores to address cell-type heterogeneity, cellular contamination and allele-specific methylation. Most of the measures were sensitive in detecting DNA methylation heterogeneity in these scenarios, while we detected differences in susceptibility to technical bias. Using recently published DNA methylation profiles of Ewing ...
In this study we present the first pooled analysis of genome-wide DNA methylation data from HM450K in HNSCCs. Compared with the largest cohort (TCGA) for which HM450K data were available, the pooled cohorts have 43% more HPV(+) cases analysed (63 vs 36), leading to a prevalence of 19% of HPV(+) cases. Moreover, many head and neck organs are included, allowing an assessment of HPV methylation signatures in different anatomic sites. Globally, our results show that HPV has a specific and genome-wide effect in shaping the DNA methylome of HNSCCs that is independent of other known major risk factors, such as tobacco smoking and alcohol consumption. Our results are similar to a recent report based on the analysis of the whole TCGA cohort [29]. The authors identified five subclusters of HNSSC based on DNA methylation patterns (528 samples), four HPV(-) clusters and one HPV(+) cluster [29].. Previous works reported aberrant hypermethylation in gene promoters of HPV(+) oropharyngeal cancer cases [2, 3, ...
TY - JOUR. T1 - Aberrant DNA methylation status in human uterine leiomyoma. AU - Yamagata, Yoshiaki. AU - Maekawa, Ryo. AU - Asada, Hiromi. AU - Taketani, Toshiaki. AU - Tamura, Isao. AU - Tamura, Hiroshi. AU - Ogane, Jun. AU - Hattori, Naka. AU - Shiota, Kunio. AU - Sugino, Norihiro. PY - 2009. Y1 - 2009. N2 - Aberrant DNA methylation has been implicated in tumorigenesis. This study was undertaken to establish the genome-wide DNA methylation profile in uterine leiomyomas and to investigate whether DNA methylation status is altered in uterine leiomyomas. For this purpose, restriction landmark genomic scanning (RLGS) was performed on a paired sample of leiomyoma and adjacent normal myometrium. The RLGS profile revealed 29 aberrant methylation spots (10 methylated and 19 demethylated) in leiomyoma in comparison with myometrium. One of the differently methylated genomic loci was newly identified as GS20656 from the human genome sequence database. In 9 of the 10 paired samples, the DNA methylation ...
Proper propagation of epigenetic information during somatic cell divisions is critical for preserving gene expression patterns and cellular identity. However, the molecular mechanisms responsible for faithful inheritance of epigenetic marks are still poorly understood. In this thesis work, I have studied the inheritance of DNA methylation patterns through somatic divisions, focusing on the role of DNA methyltransferases 3A and 3B in this process.; DNA methylation patterns are established during development and then maintained through multiple somatic cell divisions by co-operative activity of the de novo and maintenance DNA methyltransferases - DNMT3A/3B and DNMT1, respectively. A key question that remains unresolved is how the de novo DNMT3A/3B enzymes assist in faithful inheritance of methylation patterns in somatic cells while guarding against aberrant de novo DNA methylation. Using sucrose density gradient analyses of fractionated chromatin, I have shown that almost all of the cellular ...
Bisulfite sequencing is widely employed to study the role of DNA methylation in disease; however, the data suffer from biases due to coverage depth variability. Imputation of methylation values at low-coverage sites may mitigate these biases while also identifying important genomic features associated with predictive power. Here we describe BoostMe, a method for imputing low-quality DNA methylation estimates within whole-genome bisulfite sequencing (WGBS) data. BoostMe uses a gradient boosting algorithm, XGBoost, and leverages information from multiple samples for prediction. We find that BoostMe outperforms existing algorithms in speed and accuracy when applied to WGBS of human tissues. Furthermore, we show that imputation improves concordance between WGBS and the MethylationEPIC array at low WGBS depth, suggesting improved WGBS accuracy after imputation. Our findings support the use of BoostMe as a preprocessing step for WGBS analysis.
TY - JOUR. T1 - A systematic study of normalization methods for Infinium 450K methylation data using whole-genome bisulfite sequencing data. AU - Wang, Ting. AU - Guan, Weihua. AU - Lin, Jerome. AU - Boutaoui, Nadia. AU - Canino, Glorisa. AU - Luo, Jianhua. AU - Celedón, Juan Carlos. AU - Chen, Wei. N1 - Funding Information: This study was supported by the Competitive Medical Research Fund (WC) from the University of Pittsburgh, and by grants HL07996 and HL117191 (JCC) from the US. National Institutes of Health.. PY - 2015/1/1. Y1 - 2015/1/1. N2 - DNA methylation plays an important role in disease etiology. The Illumina Infinium HumanMethylation450 (450K) BeadChip is a widely used platform in large-scale epidemiologic studies. This platform can efficiently and simultaneously measure methylation levels at ∼480,000 CpG sites in the human genome in multiple study samples. Due to the intrinsic chip design of 2 types of chemistry probes, data normalization or preprocessing is a critical step to ...
This study aimed to assess the effects of PAE on genome-wide DNA methylation patterns and identify an epigenetic signature of FASD, using a large cohort of human subjects. Significant changes to the DNA methylation profiles in BECs of children with FASD compared to age- and sex-matched typically developing controls were identified, with 658 CpGs displaying significantly altered DNA methylation levels, of which 41 had a ,5 % methylation change. Moreover, 101 DMRs containing two or more sequential DM CpGs were identified throughout the genome, spanning 95 different genes, overlapping with several from the initial differential methylation analysis at single CpG level. The majority of DM genes were highly expressed in postmortem brain samples from the Allen Brain Institute. Moreover, BEC and independent cortical samples showed relatively high concordance of DNA methylation levels. As discussed in more detail below, several lines of evidence converge to support the validity of our data. First, a ...
Sequencing-based approaches have led to new insights about DNA methylation. While many different techniques for genome-scale mapping of DNA methylation have been employed, throughput has been a key limitation for most. To further facilitate the mapping of DNA methylation, we describe a protocol for gel-free multiplexed reduced representation bisulfite sequencing (mRRBS) that reduces the workload dramatically and enables processing of 96 or more samples per week. mRRBS achieves similar CpG coverage to the original RRBS protocol, while the higher throughput and lower cost make it better suited for large-scale DNA methylation mapping studies, including cohorts of cancer samples. ...
CpG island methylator phenotype (CIMP) involves the targeting of multiple genes by promoter hypermethylation. Telomerase plays an important role in the development of cellular immortality and oncogenesis. To gain insight into the role of epigenetic aberration of telomerase-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in HCC. We examined the promoter methylation status of 9 genes associated with telomerase activity in 120 HCC, 120 cirrhosis tissues and 10 normal liver tissues by methylation-specific PCR. Assay of telomerase activity was by TRAP-ELISA. The frequency of promoter methylation of each gene was P21 63.3%, P15 42.5%, P16 62.5%, P53 14.2%, RB 32.5%, P27 48.3%, WTI 54.2%, E2F-1 70.8% and P300 65.8% of 120 HCC. Methylation status of P21, P15, P16, WTI and E2F-1 was significantly associated with HCC and nontumor tissues (p | 0.05). CIMP+ was detected in 61.7% (74/120) HCC and 15% (18/120) cirrhosis tissues, no CIMP+ was present in normal liver tissues (p | 0.001).
TY - JOUR. T1 - DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. AU - Stefan, Mihaela. AU - Zhang, Weijia. AU - Concepcion, Erlinda. AU - Yi, Zhengzi. AU - Tomer, Yaron. PY - 2014/5. Y1 - 2014/5. N2 - Type 1 diabetes (T1D) shows ~40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional ...
Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. was achieved specifically through Tet3-mediated hydroxymethylation. Collectively our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis. In recent years epigenetics have emerged as determinants of fibrosis in the kidney (and other tissues as well).1-5 Furthermore epigenetics have been implied to contribute to the individual susceptibilities of CKD patients to develop fibrosis.1-3 Among the known epigenetic mechanisms methylation of CpG island promoters (referred to as DNA methylation) is the most potent to silence transcription of affected genes.6 Because transcriptional silencing of affected genes has been shown to causally contribute to fibroblast activation and Sapitinib fibrogenesis inhibition or reversal of such aberrant methylation is considered beneficial for the kidney.3 Although in ...
CpG island hypermethylation is an epigenetic control aberration that is important for gene inactivation in cancer cells. Hypermethylation of CpG islands has been described in almost every type of tumor. Many important cellular pathways, such as DNA repair (hMLH1, for example), cell cycle (p14ARF), apoptosis (DAPK), cell adherence (CDH1, CDH13), are inactivated by this epigenetic lesion. Hypermethylation is linked to methyl-binding proteins, DNA methyltransferases and histone deacetylase, but the degree to which this process selectively silences tumor suppressor genes continues to remain a vibrant field of study. The list for hypermethylated genes is growing and functional and genetic studies are being performed to determine which hypermethylation events are relevant for tumorigenesis. Basic as well as translational research will be needed to understand the mechanisms and roles of CpG island hypermethylation in cancer. The first discovery of methylation in a CpG island of a tumor suppressor gene ...
Restriction landmark genomic scanning (RLGS) has been used to study aberrant CpG island methylation in cancer for more than ten years. This approach remains one of the most reliable ways to characterize CpG island hypermethylation in cancer and has been used both to characterize differences in aberrant methylation phenotypes and also to identify tumor suppressor genes. Not only have known tumor suppressor genes like Cdkn2a (p16), Itga4 (α 4-integrin) [1], and Igfbp7 [2] been identified as targets of aberrant methylation in cancer by RLGS, but also novel tumor suppressor genes such as TCF21 [3], SLC5A8 [4], ID4 [5], BMP3B [6], and SOCS1 [7] have been identified by RLGS.. RLGS is a two-dimensional gel electrophoresis method [8] that allows detection of DNA methylation if a methylation sensitive landmark enzyme such as NotI is used. Up to 2,000 end-labeled landmark sites are displayed in a single RLGS profile. The labeling of the sites is based on incorporation of radionucleotides into the NotI ...
Southern analysis has shown that DNA from 25% of primary estrogen receptor (ER) α-negative breast tumors displays aberrant methylation at one site within the ER gene CpG island. To examine more sites and increase sensitivity, we developed a methylation-specific PCR assay to map methylation of the entire ER CpG island. The island was unmethylated in normal breast tissue and ER-positive breast cancer cell lines, but extensively methylated in all ER-negative cell lines and breast tumors examined. In addition, some of the ER-positive/progesterone receptor-negative and ER-positive/progesterone receptor-positive tumors (about 70% and 35%, respectively) displayed methylation of the ER CpG island, suggesting that this heterogeneity within tumor cell populations could potentially shed light on the etiology of ER-negative recurrent tumors arising from ER-positive tumors.. ...
Stress and antidepressant treatment can modulate DNA methylation in promoter region of genes related to neuroplasticity and mood regulation, thus implicating this epigenetic mechanism in depression neurobiology and treatment. Accordingly, systemic administration of DNA methyltransferase (DNMT) inhibitors induces antidepressant-like effects in rodents. DNA methylation is conveyed by DNMT 1, 3a and 3b isoforms, which are differentially expressed in the brain. In order to investigate if the behavioral effects of antidepressants could be associated with changes in DNA methylation and DNMT expression, we investigated the effects induced by acute and repeated antidepressant treatment on DNA methylation and DNMT expression (1, 3a and 3b isoforms) in different brain regions of rats exposed to a stress model of depression, the learned helplessness (LH). Therefore, rats were exposed to pretest and treated with one or seven injections of vehicle or imipramine (15 mg.kg-1), with test session performed one ...
TY - JOUR. T1 - Epigenetic regulation of multidrug resistance 1 gene expression. T2 - profiling CpG methylation status using bisulphite sequencing.. AU - Baker, Emma K. AU - El-Osta, Assam. PY - 2010. Y1 - 2010. N2 - Methylation of CpG dinucleotides is one of the major epigenetic processes involved in the regulation of gene expression. Catalyzed by DNA methyltransferases, hypermethylation of CpG islands in promoter regions is typically associated with gene silencing. DNA methylation plays an important role in normal differentiation, development, and maintenance of genomic stability, with aberrant CpG methylation being linked with a number of disease states. Three CpG islands within a 1.15- kb region characterize the chromatin landscape surrounding the transcriptional start site of the multidrug resistance 1 (MDR1) gene. We and others have demonstrated that hypermethylation of this region is correlated with MDR1 gene silencing and the inability of chemotherapeutic agents to activate MDR1 ...
TY - JOUR. T1 - Epigenetic variation in monozygotic twins. T2 - A genome-wide analysis of DNA methylation in buccal cells. AU - van Dongen, Jenny. AU - Ehli, Erik A.. AU - Slieker, Roderick C.. AU - Bartels, Meike. AU - Weber, Zachary M.. AU - Davies, Gareth E.. AU - Slagboom, P. Eline. AU - Heijmans, Bastiaan T.. AU - Boomsma, Dorret I.. PY - 2014/1/1. Y1 - 2014/1/1. N2 - DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ) twins offers a unique experimental design to examine the extent to which such variation is related to individual-specific environmental influences and stochastic events or to familial factors (DNA sequence and shared environment). We measured genome-wide DNA methylation in buccal samples from ten MZ pairs (age 8-19) using the Illumina 450k array and examined twin correlations for methylation ...
Alterations in the methylation patterns of promoter CpG islands have been associated with the transcriptional inhibition of genes in many human cancers. These epigenetic alterations could be used as molecular markers for the early detection of cancer-that is, while potentially curable according to current therapeutic strategies. In prostate cancer, GSTP1 hypermethylation is the most common epigenetic alteration, and can be detected in up to 90% of cases. Thus, screening for methylation of other loci would probably increase the number of primary tumours amenable to screening. Moreover, previous studies have shown that the endothelin B receptor (EDNRB) gene is abnormally methylated in a high proportion of prostate tumours ( approximately 70%).. To investigate the potential use of EDNRB gene hypermethylation as a prostate cancer specific marker.. Methylation specific polymerase chain reaction (MSP) for the promoter region of EDNRB was performed on prospectively collected tissue samples from 48 ...
Imprinted genes are expressed predominantly from either their paternal or their maternal allele. To date, all imprinted genes identified in plants are expressed in the endosperm. In Arabidopsis thaliana, maternal imprinting has been clearly demonstrated for the Polycomb group gene MEDEA (MEA) and for FWA. Direct repeats upstream of FWA are subject to DNA methylation. However, it is still not clear to what extent similar cis-acting elements may be part of a conserved molecular mechanism controlling maternally imprinted genes. In this work, we show that the Polycomb group gene FERTILIZATION-INDEPENDENT SEED2 (FIS2) is imprinted. Maintenance of FIS2 imprinting depends on DNA methylation, whereas loss of DNA methylation does not affect MEA imprinting. DNA methylation targets a small region upstream of FIS2 distinct from the target of DNA methylation associated with FWA. We show that FWA and FIS2 imprinting requires the maintenance of DNA methylation throughout the plant life cycle, including male ...
Background: The risk of developing Barretts esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body-mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influence the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina). Results: We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to
Cytosine DNA methylation is a heritable process which plays important roles in regulating development throughout the life cycle of an organism. Although methylation of nuclear DNA has been studied extensively, little is known about the state and role of DNA methylation in chloroplast genomes, especially in marine algae. Here, we have applied an integrated approach encompassing whole-genome bisulfite sequencing, methylated DNA immunoprecipitation, gene co-expression networks and photophysiological analyses to provide evidence for the role of chloroplast DNA methylation in a marine alga, the multicellular brown alga Saccharina japonica. Although the overall methylation level was relatively low in the chloroplast genome of S. japonica, gametophytes exhibited higher methylation levels than sporophytes. Gene-specific bisulfite-cloning sequencing provided additional evidence for the methylation of key photosynthetic genes. Many of them were highly expressed in sporophytes whereas genes involved in ...
We have recently identified HOP hoemobox (HOPX) as a tumor suppressor gene candidate, characterized by tumor-specific promoter DNA hypermethylation in human cancers, and it can remarkably inhibit tumors aggressive phenotypes. In this current study, we for the first time examined methylation level of HOPX and tested the functional relevance in pancreatic cancer (PC). Clinical features of HOPX promoter hypermethylation was investigated in 89 PC tissues, and immunohistochemistry was added. We also examined its functional relevance in phenotype assays such as soft agar, proliferation, invasion, and cell cycle analysis. PC tissues had HOPX gene hypermethylation as compared to the corresponding normal pancreas tissues, and its uniqueness was robust to discriminate tumor from normal tissues (AUC = 0.85, P | 0.0001). Unexpectedly, HOPX was increased in expression in tumor tissues, and immunohistochemistry revealed its predominant expression in the Langerhans islet cells, where HOPX was reduced in expression
We identified differential methylation by tumor histology in a series of pediatric GCTs, with evidence that YSTs exhibit promoter hypermethylation in a large number of cancer-related genes while germinomas and teratomas do not. These CpG loci were not hypermethylated in the normal adjacent tissue from two patients with YSTs, suggesting that methylation patterns also distinguish yolk sac tumor tissue from normal ovary or testis tissue. Four pathways, most notably a human embryonic stem cell pathway, were over-represented among the CpG loci that were hypermethylated in YSTs. A smaller number of CpG loci exhibited significantly different methylation in a comparison of mature and immature teratomas, however these loci were strikingly enriched for genes associated with embryonic stem cell pluripotency and developmental signaling pathways, such as PTEN, PDGF and NF-κB. In addition, immature teratomas were enriched for differential methylation of genes involved in axonal guidance signaling, reflecting ...
Background: Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers. Methods: The quantitative methylation analysis was performed using the SEQUENOMs EpiTYPER (TM) assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results: The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for ...
TY - JOUR. T1 - Specific 5′CpG island methylation signatures of FHIT and p16 genes and their potential diagnostic relevance in Indian breast cancer patients. AU - Naqvi, Raza A. AU - Hussain, Arif. AU - Raish, Mohmammad. AU - Noor, Afshan. AU - Shahid, Mohammad. AU - Sarin, Ritu. AU - Kukreti, Himani. AU - Khan, Nida Jameel. AU - Ahmad, Shandar. AU - Deo, Suryanarayan V.S.. AU - Husain, Syed Akhtar. AU - Pasha, Syed Tazeen. AU - Basir, Seemi Farhat. AU - Shukla, Nootan Kumar. PY - 2008/9/1. Y1 - 2008/9/1. N2 - Even after tremendous molecular studies, early detection, more accurate and sensitive diagnosis, and prognosis of breast cancer appear to be a riddle so far. To stab the enigma, this study is designed to envisage DNA methylation signatures as cancer-specific and stage-specific biomarkers in Indian patients. Rigorous review of scattered scientific reports on aberrant DNA methylation helped us to select and analyze a potential tumor suppressor gene pair (FHIT and p16 genes) in breast ...
The human CGGBP1 binds to GC-rich regions and interspersed repeats, maintains homeostasis of stochastic cytosine methylation and determines DNA-binding of CTCF. Interdependence between regulation of cytosine methylation and CTCF occupancy by CGGBP1 remains unknown. By analyzing methylated DNA-sequencing data obtained from CGGBP1-depleted cells, we report that some transcription factor-binding sites, including CTCF, resist stochastic changes in cytosine methylation. By analysing CTCF-binding sites we show that cytosine methylation changes at CTCF motifs caused by CGGBP1 depletion resist stochastic changes. These CTCF-binding sites are positioned at locations where the spread of cytosine methylation in cis depends on the levels of CGGBP1. Our findings suggest that CTCF occupancy and functions are determined by CGGBP1-regulated cytosine methylation patterns.
We performed a comparative analysis of the genome-wide DNA methylation profiles from three human embryonic stem cell (HESC) lines. It had previously been shown that HESC lines had significantly higher non-CG methylation than differentiated cells, and we therefore asked whether these sites were conserved across cell lines. We find that heavily methylated non-CG sites are strongly conserved, especially when found within the motif TACAG. They are enriched in splice sites and are more methylated than other non-CG sites in genes. We next studied the relationship between allele-specific expression and allele-specific methylation. By combining bisulfite sequencing and whole transcriptome shotgun sequencing (RNA-seq) data we identified 1,020 genes that show allele-specific expression, and 14% of CG sites genome-wide have allele-specific methylation. Finally, we asked whether the methylation state of transcription factor binding sites affects the binding of transcription factors. We identified variations in
TY - JOUR. T1 - Promoter hypermethylation of CIDEA, HAAO and RXFP3 associated with microsatellite instability in endometrial carcinomas. AU - Huang, Yi Wen. AU - Luo, Jingqin. AU - Weng, Yu I.. AU - Mutch, David G.. AU - Goodfellow, Paul J.. AU - Miller, David S.. AU - Huang, Tim H.M.. N1 - Copyright: Copyright 2010 Elsevier B.V., All rights reserved.. PY - 2010/5. Y1 - 2010/5. N2 - Objective: DNA promoter methylation is an epigenetic phenomenon for long-term gene silencing during tumorigenesis. The purpose of this study is to identify novel hypermethylated loci associated with clinicopathologic variables in endometrioid endometrial carcinomas. Methods: To find hypermethylated promoter loci, we used differential methylation hybridization coupling with microarray and further validated by combined bisulfite restriction analysis and MassARRAY assay. Methylation levels of candidate loci were corrected with clinicopathologic factors of endometrial carcinomas. Results: Increased promoter methylation ...
Barretts esophagus is a premalignant condition of the distal esophagus that increases the risk of esophageal cancer. Unfortunately, screening for Barretts esophagus currently requires endoscopy, an invasive and expensive procedure, and thus, it is not routinely performed. Moinova et al. have now demonstrated a simplified approach to screening by identifying a pair of DNA methylation markers that correlate with the presence of Barretts esophagus. The authors also invented a swallowable balloon-based device that can capture DNA samples for methylation analysis and found that it is well tolerated in patients and provides ,90% sensitivity and specificity compared to endoscopy, suggesting its potential as a screening method. ...
The purpose of this workshop is to get a deeper understanding of the use of bisulfite-treated DNA in order to analyze the epigenetic layer of DNA methylation. Advantages and disadvantages of the so-called bisulfite sequencing and its implications on data analyses will be covered. The participants will be trained to understand bisulfite-treated NGS data, to detect potential problems/errors and finally to implement their own pipelines. After this course they will be able to analyze DNA methylation and create ready-to-publish graphics.. By the end of this workshop the participants will:. be familiar with the sequencing method of ...
In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We ...
Inactivaion of tumor suppressor genes (TSGs) by promoter CpG methylation frequently occurs in tumorigenesis, even in the early stages, contributing to the initiation and progression of human cancers. Deleted in lung and esophageal cancer 1 (DLEC1), located at the 3p22-21.3 TSG cluster, has been identified frequently silenced by promoter CpG methylation in multiple carcinomas, however, no study has been performed for lymphomas yet. We examined the expression of DLEC1 by semi-quantitative reverse transcription (RT)-PCR, and evaluated the promoter methylation of DLEC1 by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) in common lymphoma cell lines and tumors. Here we report that DLEC1 is readily expressed in normal lymphoid tissues including lymph nodes and PBMCs, but reduced or silenced in 70% (16/23) of non-Hodgkin and Hodgkin lymphoma cell lines, including 2/6 diffuse large B-cell (DLBCL), 1/2 peripheral T cell lymphomas, 5/5 Burkitt, 6/7 Hodgkin and 2/3 nasal killer (NK)/T-cell
Enhanced Reduced Representation Bisulfite Sequencing is a method for the preparation of sequencing libraries for DNA methylation...
Genomic imprinting is exclusive to mammals and seed plants and refers to parent-of-origin-dependent, differential transcription. As previously shown in mammals, studies in Arabidopsis have implicated DNA methylation as an important hallmark of imprinting. The current model suggests that maternally expressed imprinted genes, such as MEDEA (MEA), are activated by the DNA glycosylase DEMETER (DME), which removes DNA methylation established by the DNA methyltransferase MET1. We report the systematic functional dissection of the MEA cis-regulatory region, resulting in the identification of a 200-bp fragment that is necessary and sufficient to mediate MEA activation and imprinted expression, thus containing the imprinting control region (ICR). Notably, imprinted MEA expression mediated by this ICR is independent of DME and MET1, consistent with the lack of any significant DNA methylation in this region. This is the first example of an ICR without differential DNA methylation, suggesting that factors ...
The maintenance methyltransferase Dnmt1 and the de novo methyltransferase Dnmt3b cooperate to maintain DNA methylation and genomic stability in the adult intestinal epithelium.
© 2019 The Author(s) 2019. Published by Oxford University Press. Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using
Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P , 1 × 10 -7, range P = 9.2 × 10 -8 to 6.0 × 10 -46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P , 0.05), and show that sentinel methylation markers identify gene ...
Precise mapping of DNA methylation patterns in CpG islands has become essential for understanding diverse biological processes such as the regulation of imprinted genes, X chromosome inactivation, and tumor suppressor gene silencing in human cancer. We describe a new method, MSP (methylation-specific PCR), which can rapidly assess the methylation status of virtually any group of CpG sites within a CpG island, independent of the use of methylation-sensitive restriction enzymes. This assay entails initial modification of DNA by sodium bisulfite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with primers specific for methylated versus unmethylated DNA. MSP requires only small quantities of DNA, is sensitive to 0.1% methylated alleles of a given CpG island locus, and can be performed on DNA extracted from paraffin-embedded samples. MSP eliminates the false positive results inherent to previous PCR-based approaches which relied on differential ...
To cast light on the contribution of methylation to genesis of ulcerative colitis (UC)-associated tumors, promoter methylation and expression of O6-methylguanine DNA methyltransferase (MGMT), hMLH1, p16INK4, and E-cadherin were examined in 14 low-grade dysplasias (LGDs), 15 high-grade dysplasias (HGDs), and 14 adenocarcinomas associated with UC and, for comparison, in 30 sporadic adenomas with LGD, 30 adenomas with HGD, and 60 adenocarcinomas, using methylation-specific polymerase chain reaction and immunohistochemical analysis. The frequency of MGMT and hMLH1 methylation in UC-associated tumors was low, with a significant difference between HGD and sporadic adenomas with HGD of the left hemicolon. The methylation frequency of p16INK4 in UC-associated tumors was also relatively low compared with sporadic colonic tumors. For E-cadherin, methylation was limited in both types of tumor. Decrease of expression of MGMT, hMLH1, and p16INK4 was significantly correlated with methylation. Thus, compared ...