scholarly journals The Competition between DNA Methylation and Demethylation is Associated with Transcription Regulation and Tumorigenesis

2021 ◽  
Author(s):  
Wei Li ◽  
Jiejun Shi ◽  
Jianfeng Xu ◽  
Yiling Chen ◽  
Jingyi Jessica Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Regulation ◽  
Tumor Suppressor Genes ◽  
Strong Association ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Chromatin Accessibility ◽  
Strongly Correlated ◽  
Average Methylation ◽  
Tet Enzymes

Abstract The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, their competition effect remains elusive. Here, we quantify the competition between DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying methylation competition by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation competition is strongly correlated with gene expression. In particular, during tumorigenesis, the elevation of methylation competition is associated with the repression of 40 ~ 60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation competition can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation competition represents a novel methylation metric important for transcription regulation and tumorigenesis and is largely distinct from conventional metrics, such as average methylation and methylation variation.

scholarly journals The concurrence of DNA methylation and demethylation is associated with transcription regulation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiejun Shi ◽  
Jianfeng Xu ◽  
Yiling Elaine Chen ◽  
Jason Sheng Li ◽  
Ya Cui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Regulation ◽  
Strong Association ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Chromatin Accessibility ◽  
Strongly Correlated ◽  
Average Methylation ◽  
Tet Enzymes

AbstractThe mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying ‘methylation concurrence’ by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.

ABERRANT DNA METHYLATION AS A CANCER-INDUCING MECHANISM

2005 ◽  
Vol 45 (1) ◽  
pp. 629-656 ◽  
Author(s):  
Manel Esteller
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Cpg Island ◽  
Gene Mutations ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Tumor Type ◽  
Suppressor Genes ◽  
Aberrant Dna Methylation

Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16INK4a, BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation “invades” the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.

PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

2019 ◽  
Vol 78 (10) ◽  
pp. 1420-1429 ◽  
Author(s):  
Xiaobo Zhu ◽  
Fang Chen ◽  
Ke Lu ◽  
Ai Wei ◽  
Qing Jiang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Knockout Mice ◽  
Cartilage Damage ◽  
Critical Role ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Peroxisome Proliferator

ObjectivesOsteoarthritis (OA) is the most common degenerative joint disease in aged population and its development is significantly influenced by aberrant epigenetic modifications of numerous OA susceptible genes; however, the precise mechanisms that DNA methylation alterations affect OA pathogenesis remain undefined. This study investigates the critical role of epigenetic PPARγ (peroxisome proliferator–activated receptor-gamma) suppression in OA development.MethodsArticular cartilage expressions of PPARγ and bioactive DNA methyltransferases (DNMTs) from OA patients and mice incurred by DMM (destabilisation of medial meniscus) were examined. DNA methylation status of both human and mouse PPARγ promoters were assessed by methylated specific PCR and/or bisulfite-sequencing PCR. OA protections by a pharmacological DNA demethylating agent 5Aza (5-Aza-2'-deoxycytidine) were compared between wild type and PPARγ knockout mice.ResultsArticular cartilages from both OA patients and DMM mice display substantial PPARγ suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPARγ promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPARγ promoter hypermethylation, recovered the PPARγ loss and effectively attenuated the cartilage damage in OA mice. 5Aza also inhibited the OA-associated excessive inflammatory cytokines and deficit anti-oxidant enzymes, which were blocked by a specific PPARγ inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPARγ knockout mice.ConclusionEpigenetic PPARγ suppression plays a key role in OA development and PPARγ preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.

scholarly journals Integrative Omics analyses reveal epigenetic memory in diabetic renal cells regulating genes associated with kidney dysfunction.

2020 ◽  
Author(s):  
Ada Admin ◽  
Anita Bansal ◽  
Sreeram Balasubramanian ◽  
Sangeeta Dhawan ◽  
Amy Leung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Target Genes ◽  
Major Complication ◽  
Promoter Hypermethylation ◽  
Chromatin Accessibility ◽  
Metabolic Memory ◽  
Epigenetic Memory ◽  
Motif Analysis

Diabetic kidney disease (DKD) is a major complication of diabetes and the leading cause of end-stage renal failure. Epigenetics has been associated with metabolic memory, in which prior periods of hyperglycemia enhance the future risk of developing DKD despite subsequent glycemic control. To understand the mechanistic role of such epigenetic memory in human DKD and identify new therapeutic targets, we profiled gene expression, DNA methylation, and chromatin accessibility in kidney proximal tubule epithelial cells (PTECs) derived from non-diabetic and Type-2 diabetic (T2D) subjects. T2D-PTECs displayed persistent gene expression and epigenetic changes with and without TGFβ1 treatment, even after culturing <i>in vitro</i> under similar conditions as non-diabetic PTECs, signified by deregulation of fibrotic and transport associated genes (TAGs). Motif-analysis of differential DNA methylation and chromatin accessibility regions associated with genes differentially regulated in T2D revealed enrichment for SMAD3, HNF4A, and CTCF transcription factor binding sites. Furthermore, the downregulation of several TAGs in T2D (including <i>CLDN10</i>, <i>CLDN14</i>, <i>CLDN16</i>, <i>SLC16A2</i>, <i>SLC16A5</i>) was associated with promoter hypermethylation, decreased chromatin accessibility and reduced enrichment of HNF4A, histone H3-lysine-27-acetylation, and CTCF. Together, these integrative analyses reveal epigenetic memory underlying the deregulation of key target genes in T2D-PTECs that may contribute to sustained renal dysfunction in DKD.

scholarly journals DNA Methylation Is Responsive to the Environment and Regulates the Expression of Biosynthetic Gene Clusters, Metabolite Production, and Virulence in Fusarium graminearum

2021 ◽  
Vol 1 ◽  
Author(s):  
Christopher Bonner ◽  
Amanda Sproule ◽  
Owen Rowland ◽  
David Overy ◽  
Rajagopal Subramaniam
Keyword(s):  
Dna Methylation ◽  
Fusarium Graminearum ◽  
External Environment ◽  
Gene Clusters ◽  
Dna Methyltransferases ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Mutant Strains ◽  
Average Methylation ◽  
Methylation Patterns

Histone modifications play a significant role in the regulation of biosynthetic gene clusters (BGCs) in the phytopathogen Fusarium graminearum, by contrast, epigenetic regulation by DNA methyltransferases (DNMTs) is less documented. In this study, we characterized two DNMTs (FgDIM-2 and FgRID) in F. graminearum, with homologies to “Deficient in methylation” (DIM-2) and “Repeat-induced point (RIP) deficient” (RID) from Neurospora. The loss of DNMTs resulted in not only a decrease in average methylation density in the nutrient-poor, compared to nutrient-rich conditions, but also differences in the genes expressed between the WT and the DNMT mutant strains, implicating the external environment as an important trigger in altering DNA methylation patterns. Consequently, we observed significant changes in the regulation of multiple BGCs and alterations in the pathogenicity of the fungus.

Promoter Methylation of Multiple Genes in Germinal Center Hyperplasia and Lymphomas of Germinal Center Origin

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4487-4487
Author(s):  
Jose M Paz-Carreira ◽  
Raquel Losada ◽  
Arantxa Garcia-Rivero ◽  
Augusto Alvarez ◽  
Fernando Bal ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
B Cell ◽  
Promoter Methylation ◽  
Germinal Center ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Epigenetic Mechanism ◽  
Suppressor Genes

Abstract INTRODUCTION. Germinal centers (GC) are unique sites in peripheral lymphoid tissue where clonal selection of B cells takes place. This occurs as a response to stimulation by various antigens originating, sometimes, follicular hyperplasia (FH). GC have been known as a major source of B-cell lymphomas including follicular (FL) and diffuse large cell (DLCL). DNA methylation of tumor-suppressor genes is a mechanism of gene silencing involved in the pathogenesis of FL and DLCL. Much less is known about the role of methylation in FH. We determined the methylation status of 6 tumor-suppressor genes in 43 patients with FH, 18 patients with FL and 49 patients with DLCL in order to see the differential implication of this epigenetic mechanism in the pathological and the physiological development of GC. MATERIAL AND METHODS. Genomic DNA extracted from paraffin-embedded samples of 43 FH, 18 FL and 49 DLCL after being treated with EZ DNA-Methylation Kit (Zymo Research) with the manufacturer’s instructions, were analyzed by methylation-specific polymerase chain-reaction to determine promoter hypermethylation of DAP-k, SHP1, Rarβ, p14, SHP1, MGMT and PDRM1. All samples were obtained mostly from lymph nodes and tonsils. Diagnosis was based on morphology and immunohistochemistry analysis. All cases were matched for age, sex and ethnic origin. RESULTS: DAP-k promoter methylation occurred with higher frequency in FL(89%) than in DLCL(78%) and FH(40%). SHP1 was methylated in 61% of FL, 58% of FH and 23% of DLCL. RARb was methylated in 67% of FL patients, 30% of DLCL and only 12% of FH. Eight (44%) FL, seventeen (35%) DLCL and four (10%) BFH patients showed MGMT methylation. Promoter hypermethylation of p14 was detected only in 5 (12%) FH, 2 (4%) DLCL and none FL patients. Methylation of PRMD1 was present only in 1 (6%) FL, 2 (6%) DLCL and 1 (4%) FH samples. CONCLUSIONS. Inactivacion of DAP-K and SHP1 is present in B-cell malignancies, DLCL and FL, and BFH. Therefore, it may represent a physiologic event conferring a temporal survival advantage necessary for a GC hyperplastic response. Inactivation of the retinoic acid response through the methylation of Rarâ is significantly more frequent in lymphomas than in FH. As reported in other tumors methylation of MGMT is more frequent in lymphomas than in FH. With our data methylation of Cyclin dependent kinase inhibitors p14 is not a differential pathogenic event in lymphomas of GC origin, in fact it is more frequent in FH. Promoter Methylation of PDRM1 is not the mechanism involved in lymphomagenesis in FL and DLCL, the two FH positive deserve further follow-up to determine its significance.

scholarly journals Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes

2020 ◽  
Vol 10 (9) ◽  
pp. 611
Author(s):  
Kalaiselvi Sivalingam ◽  
Thangavel Samikkannu
Keyword(s):  
Dna Methylation ◽  
Nuclear Dna ◽  
Epigenetic Modification ◽  
Neuroprotective Effect ◽  
Dna Methyltransferases ◽  
Epigenetic Changes ◽  
Nootropic Drug ◽  
The Central Nervous System ◽  
Tet Enzymes ◽  
The Impact

Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining genomic integrity in the central nervous system (CNS). However, the impact of cocaine-mediated epigenetic changes in astrocytes has not yet been elucidated. In this study, we explored the neuroprotective effect of piracetam against cocaine-induced epigenetic changes in DNA methylation in astrocytes. To study our hypothesis, we exposed human astrocytes to cocaine alone or in combination with the nootropic drug piracetam. We examined the expression of the DNA methyltransferases (DNMTs) DNMT-1, DNMT-3A, and DNMT-3B; global DNA methylation levels of 5-methycytosine (5-mC); and induction of ten–eleven translocation (TET) enzymes in astrocytes. In addition, we analyzed mtDNA methylation by targeted next-generation bisulfite sequencing. Our data provide evidence that cocaine impairs DNMT activity and thereby has impacts on mtDNA, which might contribute to the neurodegeneration observed in cocaine users. These effects might be at least partially prevented by piracetam, allowing neuronal function to be maintained.

scholarly journals Pan-Cancer Analysis of FURIN as a Potential Prognostic and Immunological Biomarker

2021 ◽  
Vol 8 ◽  
Author(s):  
Bolun Zhou ◽  
Shugeng Gao
Keyword(s):  
Dna Methylation ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Strong Association ◽  
Strongly Correlated ◽  
Calcium Dependent ◽  
Free Interval ◽  
Tumor Mutational Burden ◽  
Pan Cancer

BackgroundFurin is a calcium-dependent protease that processes various precursor proteins through diverse secretory pathways. The deregulation of FURIN correlated with the prognosis of patients in numerous diseases. However, the role of FURIN in human pan-cancer is still largely unknown.MethodsMultiple bioinformatic methods were employed to comprehensively analyze the correlation of FURIN expression with prognosis, mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB), DNA methylation, tumor immune infiltration, and common immune checkpoint inhibitors (ICIs) from the public database, and aim to evaluate the potential prognostic value of FURIN across cancers.ResultsFURIN was aberrantly expressed and was strongly correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Moreover, survival analysis across cancers revealed that FURIN expression was correlated with overall survival (OS) in four cancers, disease-specific survival (DSS) in five cancers, progression-free interval (PFI) in seven cancers, and disease-free interval (DFI) in two cancers. Also, FURIN expression was related to immune cell infiltration in 6 cancers and ImmuneScore/StromalScore in 10 cancers, respectively. In addition, FURIN expression also showed strong association between expression levels and immune checkpoint markers in three cancers.ConclusionFURIN can serve as a significant prognostic biomarker and correlate with tumor immunity in human pan-cancer.

scholarly journals DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

2018 ◽  
Vol 179 (3) ◽  
pp. 153-160 ◽  
Author(s):  
E B Conemans ◽  
L Lodewijk ◽  
C B Moelans ◽  
G J A Offerhaus ◽  
C R C Pieterman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Tumor Suppressor Genes ◽  
Gene Promoter ◽  
Pancreatic Neuroendocrine Tumor ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Suppressor Genes ◽  
Frequent Event

ObjectiveEpigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.Design and methodsMethylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.ResultsWe found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876,P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages ofCASP8in MEN1-related PanNETs (median: 59% vs 16.5%,P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5;P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869;P = 0.013). Hypermethylation ofMGMT2was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%;P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.ConclusionPromoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

scholarly journals Consistent DNA Hypermethylation Patterns in Laryngeal Papillomas

2010 ◽  
Vol 1 (2) ◽  
pp. 69-77 ◽  
Author(s):  
Josena K Stephen ◽  
Kang Mei Chen ◽  
Veena Shah ◽  
Vanessa G Schweitzer ◽  
Glendon Gardner ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Aberrant Methylation ◽  
Dna Hypermethylation ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Specific Pcr

Abstract Introduction This study examined the contribution of promoter hypermethylation to the pathogenesis of respiratory papillomatosis (RP), including recurrences (RRP) and progression to squamous cell carcinoma (SSC). Materials and methods A retrospective cohort of 25 laryngeal papilloma cases included 21 RRP, two of which progressed to SCC. Aberrant methylation status was determined using the multigene (22 tumor suppressor genes) methylation-specific multiplex ligationdependent probe amplification assay and confirmed using methylation specific PCR. Results Twenty genes had altered DNA methylation in 22 of 25 cases. Aberrant methylation of CDKN2B and TIMP3 was most frequent. Promoter hypermethylation of BRCA2, APC, CDKN2A and CDKN2B was detected in 2 RRP cases with subsequent progression to SCC. Of the 25 cases, 22 were positive for HPV-6, 2 for HPV-11 and 1 for HPV-16 and 33. Conclusion Consistent aberrant methylation of multiple tumor suppressor genes contributes to the pathogenesis of laryngeal papillomas. Persistent aberrant DNA methylation events in 2 RRP cases that progressed to cancer indicate an epigenetic monoclonal progression continuum to SCC.

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