Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis

Abstract

Subtelomeric chromatin modifications are important regulators of telomere length. We examined the subtelomeric DNA methylation status of 7q, 8q, 17q, 18p, 21q and XpYp in 32 pairs of hepatocellular carcinomas (HCCs) and their adjacent nonHCCs via methylation-specific PCR (quantified as methylation ratio). In addition, 10q was subjected to bisulfite-genomicsequencing. Telomere length was determined by Southern hybridization. In all cases, the relationship between methylation ratio and telomere length was determined. High levels of methylation ratio were found on chromosomes 7q, 18p and XpYp, whereas 8q 17q and 21q were less methylated in both HCCs and non-HCCs. Compared to non-HCCs, HCCs exhibited a higher methylation ratio on 18p and 21q, and a wider distribution of methylation ratio on 7q, 21q and 10q (p < 0.05). The methylation ratio of 18p and of 21q was negatively and positively correlated with telomere length of HCCs, respectively (p < 0.05). We evaluated changes in methylation pattern between non-HCCs and HCCs. Out of 185 sites, hypermethylation changes from non-HCC to HCC were found at 47 sites and hypomethylation changes at 31 sites. Changes in methylation pattern were observed at three to four sites among six chromosomal sites in 15 patients (47%). There was a tendency toward hypomethylation changes at 7q (p 5 0.013) and hypermethylation changes at 21q (p 5 0.057) when telomere lengthened from non-HCCs to HCCs. In summary, subtelomeric methylation patterns dynamically changed during hepatocarcinogenesis. Subtelomeric methylation at certain regions was related to telomere lengthening or shortening, suggesting an association between subtelomeric chromatin structure and telomere length regulation in human hepatocarcinogenesis.

High‐risk human papillomavirus infection associated with telomere elongation in patients with esophageal squamous cell carcinoma with poor prognosis

“…The increased presence of a cluster of CpG sites in the hTERT, TRF2, and subtelomeric promoter region of genes prompted us to investigate the importance of DNA methylation and modifications in telomerase activation and length. Recently, certain regions of subtelomeric methylation patterns related to TL underwent dynamic changes during hepatocarcinogenesis and in other human cancer cell lines . However, to the best of our knowledge, no studies to date have focused on the hTERT, TRF2, and subtelomeric DNA methylation patterns of telomerase dysfunction in ESCC with repeated detection of HPV.…”

Telomeres and telomere dynamics: relevance to cancers of the GI tract

“…Subtelomeric methylation may prompt chromatin restructuring and remodeling that may influence the telomere length variation associated with hepatocarcinogenesis [117]. …”

Optogenetic regulation of site-specific subtelomeric DNA-methylation

“…The subtelomeric CpG sites of Chr. 7q, 8q, 16p, 18p, 21q, and Xp were selected due to their unique sequences, absence of telomere like repeats, lack of sequence gaps and varying distance of the CpG sites from the telomeres and interstitial TTAGGG sequences [35, 36]. The change in the methylation status at the subtelomeric CpG sites of six chromosomes (Chr.)…”

“…Epigenetic modifications are important in maintaining the heterochromatic state of telomeric and subtelomeric regions which in turn affects the telomere length and stability in both normal and cancerous cells [18, 20, 21, 25, 35, 48, 49]. Previously, a negative correlation between subtelomeric DNA methylation and the telomere length and telomeric recombination has been established in embryonic stem cells by experimental abrogation of DNMTs [20].…”