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Global Hypomethylation (global + hypomethylation)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Aberrant DNA methylation associated with MTHFR C677T genetic polymorphism in cutaneous squamous cell carcinoma in renal transplant patients

BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2010
M.E. Laing
Summary Background, Changes in genomic DNA methylation associated with cancer include global DNA hypomethylation and gene-specific hyper- or hypomethylation. We have previously identified a genetic variant in the MTHFR gene involved in the methylation pathway which confers risk for the development of squamous cell carcinoma (SCC) in renal transplant patients. This genetic variant has also been discovered to confer SCC risk in nontransplant patients with low folate status. Objectives, To explore the methylation profile of SCC compared with adjacent non-neoplastic skin using pyrosequencing, and to elucidate whether the MTHFR polymorphism impacts upon the methylation patterns in SCC. Methods, We used pyrosequencing to evaluate global (using long interspersed nuclear element 1) and gene-specific (p16 and MGMT) methylation status in 47 SCCs and 40 adjacent autologous non-neoplastic skin samples in those with (n = 16) and without (n = 17) the MTHFR polymorphism. Results, Pyrosequencing methylation analysis revealed that SCC was hypomethylated compared with adjacent non-neoplastic skin (P < 0·04). Patients with the MTHFR polymorphism had higher levels of global methylation in tumours and non-neoplastic skin compared with those without the MTHFR polymorphism (P < 0·002). There was no association between levels of methylation in tumour and non-neoplastic skin for the genes MGMT and p16. Conclusions, Global hypomethylation appears to be a feature of SCC. Aberrant methylation of DNA appears related to polymorphisms of MTHFR. Such findings suggest that intervention in the form of demethylating agents or folate supplementation might be beneficial in the treatment or prevention of SCC. [source]

Hypermethylation of gene promoters in hematological neoplasia

HEMATOLOGICAL ONCOLOGY, Issue 4 2002
C. S. Chim
Abstract Cancer cells are associated with global hypomethylation but with focal hypermethylation of specific gene promoters organized as CpG island. DNA methyltransferases, DNMT1 and 3 (3a and 3b), have been implicated in mediating maintenance and de novo methylation. Hypermethylation of gene promoters results in the inactivation of the corresponding genes, by preclusion of the formation of the transcription complex, due to the recruitment of MBP, MeCPs and histone deacetylase. This results in the deacetylation of histone and thus a compact chromatin complex unfavourable for the initiation of transcription. This methylation-associated gene silencing has been demonstrated in various genes including tumour suppressor genes (p15, p16, p73, VHL). Therefore, gene promoter hypermethylation collaborates with other mechanisms of gene inactivation such as deletion and intragenic mutations to fulfil Knudson's hypothesis. Hypermethylation may serve as a molecular disease marker for the detection of minimal residual disease. Emerging evidence suggests a possible prognostic value of gene promoter hypermethylation. Moreover, gene hypermethylation may also serve as a target for therapeutic invention by hypomethylating agents. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap

BRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2006
Y. M. Smulders
Summary Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised via the methionine synthase pathway, nor can it be reconverted to its precursor, methylenetetrahydrofolate. Other manifestations of the methylfolate trap include cellular folate loss because of shorter 5MTHF polyglutamate chains and global hypomethylation. The methylfolate trap has never been demonstrated in humans. We describe a patient with B12 deficiency who was homozygous for the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation. We analysed red blood cell (RBC) folate vitamers and global DNA methylation by liquid chromatography (LC) in combination with tandem mass spectrometry, and 5MTHF polyglutamate length by LC-electrochemical detection. Compared to post-B12 supplementation values, homocysteine was higher (52·9 ,mol/l vs. 16·8 ,mol/l), RBC folate was lower (268·92 nmol/l vs. 501·2 nmol/l), the 5MTHF fraction of RBC folate was much higher (94·5% vs. 67·4%), polyglutamate chain length was shorter (more tetra- and pentaglutamates), and global DNA methylation was 22% lower. This is the first time that virtually all features of the methylfolate trap hypothesis have been demonstrated in a human with vitamin B12 deficiency. [source]

Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation

CANCER SCIENCE, Issue 1 2004
Atsushi Kaneda
Hypomethylation of the global genome, considered to be composed mainly of repetitive sequences, is consistently observed in cancers, and aberrant hypo- and hypermethylation of CpG islands (CGIs) in promoter regions are also observed. Since methylation alterations in unique promoter sequences and in other genomic regions have distinct consequences, we analyzed the relationship between the global hypomethylation and the hypomethylation of unique promoter CGIs using human gastric cancers. Seven of ten gastric cancer cell lines showed marked decreases in 5-methylcytosine content, which correlated with hypomethylation of the LINE1 repetitive sequence. Six of the seven cell lines showed hypomethylation in five or all of the six normally methylated CGIs in promoter regions of six genes, and this was associated with induction of aberrant expression. The remaining three cell lines without global hypomethylation showed promoter hypomethylation in one or none of the six CGIs. Frequent promoter hypomethylation, however, did not correlate with frequent promoter hypermethylation. In primary gastric cancers too, global hypomethylation was associated with hypomethylation of LINE1 repetitive sequence and promoter hypomethylation. Of 93 gastric cancers, 33 cancers with frequent promoter hypomethylation and 27 cancers with frequent promoter hypermethylation constituted different groups. These findings represent experimental evidence that frequent hypomethylation of normally methylated promoter CGIs is associated with global hypomethylation, and that these hypomethylations occur independently of frequent promoter CGI hypermethylation. (Cancer Sci 2004; 95: 58,64) [source]