scholarly journals From aging to cancer: a DNA methylation journey

2012 ◽  
Vol 3 (1) ◽  
pp. 4
Author(s):  
Natalia Puig ◽  
Ruben Agrelo
Keyword(s):  
Dna Methylation ◽  
Gene Silencing ◽  
Genomic Instability ◽  
Neoplastic Transformation ◽  
Promoter Hypermethylation ◽  
Premature Aging ◽  
Global Dna Methylation ◽  
Major Step ◽  
Normal Tissues ◽  
Epigenetic Gene Silencing

Epigenetic gene silencing through DNA promoter hypermethylation is now recognised<strong> </strong>as a major step in the neoplastic transformation of the cell. The methylation levels of several genes increase with age in normal tissues such as the prostate or colon. Genes like <em>WRN </em>or<em> LMNA </em>that are involved in progeria,a premature aging disease <em>WRN and LMNA, </em>are epigenetically inactivated in cancer. In both aging and cancer, global DNA methylation decreases, potentially accounting for the characteristic genomic instability of these processes. In this review, we will focus on how the accumulation of changes in DNA methylation during aging impact tumourigenesis.

scholarly journals Integrated Analysis of Global DNA Methylation and Transcription Reveals a Leukemia Subtype with Extreme Hypermethylation Associated with Silencing of Regulators of Differentiation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2608-2608
Author(s):  
Claudia Gebhard ◽  
Roger Mulet-Lazaro ◽  
Lucia Schwarzfischer ◽  
Dagmar Glatz ◽  
Margit Nuetzel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Research Funding ◽  
Promoter Hypermethylation ◽  
Ctcf Binding ◽  
P Value ◽  
Global Dna Methylation ◽  
Employment Equity ◽  
Equity Ownership

Abstract Acute myeloid leukemia (AML) represents a highly heterogeneous myeloid stem cell disorder classified based on various genetic defects. Besides genetic alterations, epigenetic changes are recognized as an additional mechanism contributing to leukemogenesis, but insight into the latter process remains minor. Using a combination of Methyl-CpG-Immunoprecipitation (MCIp-chip) and MALDI-TOF analysis of bisulfite-treated DNA in a cohort of 196 AML patients we previously demonstrated that (cyto)genetically defined AML subtypes, including CBFB-MYH11, AML-ETO, NPM1-mut, CEBPA-mut or IDH1/2-mut subtypes, express specific DNA-methylation profiles (Gebhard et al, Leukemia, 2018). A fraction of AML patients (5/196) displayed a unique abnormal hypermethylation profile that was completely distinct from any other AML subtype. These patients present immature leukemia (FAB M0, M1) with various chromosomal aberrations but very few mutations (e.g. no IDH1/2, KRAS, DNMT3A) that might explain the CpG island methylator phenotype (CIMP) phenotype. The CIMP patients showed high resemblance with a recently reported CEBPA methylated subgroup (Wouters et al, 2007 and Figueroa et al, 2009), which we confirmed by MCIp-chip and MALDI-TOF analysis. To explore the whole range of epigenetic alterations in the CIMP-AML patients we performed in-depth global DNA methylation and gene expression analyses (MCIp-seq and RNA-seq) in 45 AML and 12 CIMP patients from both studies. Principle component analysis and t-distributed stochastic neighbor embedding (t-SNE) revealed that CIMP patients express a unique DNA-methylation and gene-expression signature that separated them from all other AMLs. We could discriminate promoter methylation from non-promoter methylation by selecting MCIp-seq peaks within 3kb around TSS. Promoter hypermethylation was highly associated with repression of genes (PCC = -0.053, p-value = 0.00075). Hypermethylation of non-promoter regions was more strongly associated with upregulation of genes (PCC = 0.046, p-value = 4.613e-06). Interestingly, differentially methylated regions also showed a positive association with myeloid lineage CTCF binding sites (27% vs 18% expected, p-value < 2.2e-16 in a chi-square test of independence). Methylation of CTCF sites causes loss of CTCF binding, which has been reported to disrupt boundaries between so-called topologically associated domains (TADs), allowing enhancers located in a particular TAD to become accessible to genes in adjacent TADs and affect their transcription. Whether this is the case is under investigation. In this study we particularly focused on the role of hypermethylation of promoters in CIMP-AMLs. Promoters of many transcriptional regulators that are involved in the differentiation of myeloid lineages of which several are frequently mutated in AML were hypermethylated and repressed, including CEBPA, CEBPD, IRF8, GATA2, KLF4, MITF or MAFB. Notably, HMGA2, a critical regulator of myeloid progenitor expansion, exhibited the largest degree of CIMP promoter hypermethylation compared to the other AMLs, accompanied by a reduction in gene expression. Moreover, multiple members of the HOXB family and KLF1 (erythroid differentiation) were methylated and repressed as well. In addition, these patients frequently showed hypermethylation of many chromatin factors (e.g. LMNA, CHD7 or TET2). Hypermethylation of the TET2 promoter could result in a loss of maintenance DNA demethylation and therefore successive hypermethylation at CpG islands. We carried out regulome-capture-bisulfite sequencing on CIMP-AMLs compared to other AML samples and normal blood cell controls and confirmed methylation of the same transcription and chromatin factor promoters. We conclude that these leukemias represent very primitive HSCPs which are blocked in differentiation into multiple hematopoietic lineages, due to the absence of regulators of these lineages. Although the underlying cause for the extreme hypermethylation signature is still subject to ongoing studies, the consequence of promoter hypermethylation is silencing of key lineage regulators causing the differentiation arrest in these cells. We argue that these patients may particularly benefit from therapies that revert DNA methylation. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

scholarly journals Altered methionine metabolism and global DNA methylation in liver cancer: Relationship with genomic instability and prognosis

2007 ◽  
Vol 121 (11) ◽  
pp. 2410-2420 ◽  
Author(s):  
Diego F. Calvisi ◽  
Maria M. Simile ◽  
Sara Ladu ◽  
Rossella Pellegrino ◽  
Valentina De Murtas ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liver Cancer ◽  
Genomic Instability ◽  
Global Dna Methylation ◽  
Methionine Metabolism

scholarly journals Using Telomeric Length Measurements and Methylation to Understand The Karyotype Diversification of Ctenomys Minutus (A Small Fossorial Mammals)

2021 ◽  
Author(s):  
Cristina A. Matzenbacher ◽  
Juliana Silva ◽  
Ana Leticia H. Garcia ◽  
Rafael Kretschmer ◽  
Mónica Cappetta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genomic Instability ◽  
Chromosomal Instability ◽  
Diploid Number ◽  
Karyotype Evolution ◽  
Chromosomal Rearrangements ◽  
Global Dna Methylation ◽  
Methylated Dna ◽  
Significant Difference ◽  
Length Measurements

Abstract The genus Ctenomys has been widely used in karyotype evolution studies due to the variation in their diploid numbers (2n), which range from 2n = 10 to 2n = 70. Ctenomys minutus is characterized by intraspecific variation in diploid number (2n = 42, 46, 48, and 50), which makes it an interesting model to investigate the genomic instability mechanisms that have led to different cytotypes in this species. We aimed to contribute to the knowledge about telomeres’ role in chromosomal instability and global DNA methylation in the genome evolution of C. minutus. This study found that telomere length differs between cytotypes, but only for females (50a<46a,48a,42), although methylation was also higher, no significant difference was shown. It was also shown that young individuals, regardless of cytotype, had the longest telomere and the most methylated DNA, although only the last was statistically significant. Despite this, there is still much to be answered, although new cytotypes seem to have emerged within the distribution of parental cytotypes by the accumulation of different chromosomal rearrangements.

scholarly journals Expression profiling of DNA methylation-mediated epigenetic gene-silencing factors in breast cancer

2014 ◽  
Vol 6 (1) ◽  
pp. 20 ◽  
Author(s):  
Swayamsiddha Kar ◽  
Dipta Sengupta ◽  
Moonmoon Deb ◽  
Arunima Shilpi ◽  
Sabnam Parbin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Gene Silencing ◽  
Expression Profiling ◽  
Epigenetic Gene Silencing

Epigenetic Gene Silencing is a Novel Mechanism Involved in Delayed Manifestation of Radiation-Induced Genomic Instability in Mammalian Cells

2011 ◽  
Vol 175 (4) ◽  
pp. 416-423 ◽  
Author(s):  
Keiji Suzuki ◽  
Hiroko Yamaji ◽  
Shinko Kobashigawa ◽  
Rie Kawauchi ◽  
Kazutaka Shima ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Genomic Instability ◽  
Mammalian Cells ◽  
Epigenetic Gene Silencing ◽  
Radiation Induced

Global DNA Methylation is influenced by smoking behavior

2007 ◽  
Vol 40 (05) ◽  
Author(s):  
MAN Muschler ◽  
T Hillemacher ◽  
H Frieling ◽  
S Moskau ◽  
A Semmler ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Smoking Behavior ◽  
Global Dna Methylation
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