Subtelomeric DNA methylation and telomere length in human cancer cells

Lee, Myung Eun; Rha, Sun Young; Jeung, Hei Cheul; Chung, Hyun Cheol; Oh, Bong Kyeong

doi:10.1016/j.canlet.2009.02.031

Cited by 16 publications

(16 citation statements)

References 35 publications

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“…We detected changes across the entire chromosome, indicating that there was no positional preferences on the chromosome and possibly also no bias toward centromeres or telomeres. Subtelomeric regions are potentially unreliable for array based methods due to their highly repetitive DNA composition and high C + G content, and associated high methylation levels (Lee et al, 2009). Furthermore, BEDMR regions seem to occur in genic regions, in particular near genes with cancer related functions.…”

Section: Discussionmentioning

confidence: 99%

Major Chromosomal Breakpoint Intervals in Breast Cancer Co-Localize with Differentially Methylated Regions

Tang¹,

Varadan²,

Kamalakaran³

et al. 2012

Front. Oncol.

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Solid tumors exhibit chromosomal rearrangements resulting in gain or loss of multiple chromosomal loci (copy number variation, or CNV), and translocations that occasionally result in the creation of novel chimeric genes. In the case of breast cancer, although most individual tumors each have unique CNV landscape, the breakpoints, as measured over large datasets, appear to be non-randomly distributed in the genome. Breakpoints show a significant regional concentration at genomic loci spanning perhaps several megabases. The proximal cause of these breakpoint concentrations is a subject of speculation, but is, as yet, largely unknown. To shed light on this issue, we have performed a bio-statistical analysis on our previously published data for a set of 119 breast tumors and normal controls (Wiedswang et al., 2003), where each sample has both high-resolution CNV and methylation data. The method examined the distribution of closeness of breakpoint regions with differentially methylated regions (DMR), coupled with additional genomic parameters, such as repeat elements and designated “fragile sites” in the reference genome. Through this analysis, we have identified a set of 93 regional loci called breakpoint enriched DMR (BEDMRs) characterized by altered DNA methylation in cancer compared to normal cells that are associated with frequent breakpoint concentrations within a distance of 1 Mb. BEDMR loci are further associated with local hypomethylation (66%), concentrations of the Alu SINE repeats within 3 Mb (35% of the cases), and tend to occur near a number of cancer related genes such as the protocadherins, AKT1, DUB3, GAB2. Furthermore, BEDMRs seem to deregulate members of the histone gene family and chromatin remodeling factors, e.g., JMJD1B, which might affect the chromatin structure and disrupt coordinate signaling and repair. From this analysis we propose that preference for chromosomal breakpoints is related to genome structure coupled with alterations in DNA methylation and hence, chromatin structure, associated with tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Major Chromosomal Breakpoint Intervals in Breast Cancer Co-Localize with Differentially Methylated Regions

Tang¹,

Varadan²,

Kamalakaran³

et al. 2012

Front. Oncol.

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“…As the subtelomeric assembly of each chromosome arm is variable, with subtelomeric repeat sequences ranging from <10 kb to >300 kb, 64 the number of CpG and, hence, the extent of subtelomeric methylation is likely to be different among human chromosomes. Currently, subtelomeric methylation is determined by methylation‐specific PCR; 116 however, this method is limited in that the amplicon size is very small (< 200 bp), and so the result reflects the methylation status of few cytosine residues in the possible 500 kb subtelomeric region 64 . The conception of optimal methods that would allow for the definitive subtelomeric methylation status across each chromosome arm, and comparison of this status with chromosome arm–specific telomere length 117 remain important goals.…”

Section: Subtelomere Dna Methylation and Telomere Lengthmentioning

confidence: 99%

Telomere dynamics: the influence of folate and DNA methylation

Moores

Fenech

O’Callaghan

2011

Annals of the New York Academy of Sciences

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Since the suggestion of their existence, a wealth of literature on telomere biology has emerged aimed at solving the DNA end-underreplication problem identified by Olovnikov in 1971. Telomere shortening/dysfunction is now recognized as increasing degenerative disease risk. Recent studies have suggested that both dietary patterns and individual micronutrients-including folate-can influence telomere length and function. Folate is an important dietary vitamin required for DNA synthesis, repair, and one-carbon metabolism within the cell. However, the potential mechanisms by which folate deficiency directly or indirectly affects telomere biology has not yet been reviewed comprehensively. The present review summarizes recent published knowledge and identifies the residual knowledge gaps. Specifically, this review addresses whether it is plausible that folate deficiency may (1) cause accelerated telomere shortening, (2) intrinsically affect telomere function, and/or (3) cause increased telomere-end fusions and subsequent breakage-fusion-bridge cycles in the cell.

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“…In a panel of human cancer cell lines, a negative correlation between subtelomeric methylation and TL was observed (Vera et al , 2008). A subsequent study suggested that the inverse relationship between subtelomeric methylation and TL was chromosomal dependent (Lee et al , 2009). …”

Section: Introductionmentioning

confidence: 99%

The relationship between DNA methylation and telomere length in dyskeratosis congenita

et al. 2011

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SummaryThe regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE‐1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation‐negative relatives. Pearson’s correlation coefficient and linear regression models were used to evaluate the relationship between age‐standardized lymphocyte TL measured by flow FISH and % DNA methylation. No differences in % subtelomeric, LINE‐1, or pericentromeric methylation between patients with DC and relatives were noted except for an increase in % subtelomeric methylation in DC patients with a telomerase‐complex mutation (TERC, TERT, DKC1, or TCAB1) (63.0% in DC vs. 61.8% in relatives, P = 0.03). Positive correlations between TL and DNA methylation at LINE‐1 (r = 0.39, P = 0.01) and subtelomeric (r = 0.32, P = 0.05) sites were present in patients with DC. The positive correlation between TL and % LINE‐1 methylation was restricted to TINF2 mutations. In contrast, statistically nonsignificant inverse correlations between TL and % LINE‐1 (r = −0.17), subtelomeric (r = −0.20) were present in unaffected relatives. This study suggests an interaction between TL and both subtelomeric and LINE‐1 methylation, which may be altered based on mutation status of telomere biology genes.

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Subtelomeric DNA methylation and telomere length in human cancer cells

Cited by 16 publications

References 35 publications

Major Chromosomal Breakpoint Intervals in Breast Cancer Co-Localize with Differentially Methylated Regions

Major Chromosomal Breakpoint Intervals in Breast Cancer Co-Localize with Differentially Methylated Regions

Telomere dynamics: the influence of folate and DNA methylation

The relationship between DNA methylation and telomere length in dyskeratosis congenita

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