Promoter methylation, transcription, and retrotransposition of LINE-1 in colorectal adenomas and adenocarcinomas

Abstract

Background: LINE-1, Alu, and SVA elements are non-LTR retrotransposons that create approximately one-third of the human genome. The loss of tight control mechanisms on the function of mobile elements has been implicated in many human diseases. The methylation of the CpG islands of the LINE-1 promoter is one of these mechanisms. In this study, we determined the promoter methylation and the expression of LINE-1 in three stages of colorectal non-advanced adenoma, advanced adenoma, and adenocarcinoma. In addition, we analyzed the insertion of LINE-1, Alu, and SVA elements in the genome of colorectal advanced adenomas.Results: We found that the LINE-1 hypomethylation index in advanced adenoma and adenocarcinoma were significantly higher than that in non-advanced adenomas. The copy number of LINE-1 transcripts in advanced adenoma was significantly higher than that in non-advanced adenomas, and in adenocarcinomas was significantly higher than that in the advanced adenomas. Analysis of the genome of colorectal advanced adenomas revealed that at this stage de novo insertions of LINE-1, Alu, and SVA were approximately 16%, 51%, and 74%, respectively.Conclusions: Our findings showing a decreased methylation of LINE-1 promoter accompanied by the higher level of LINE-1 transcription, and de novo genomic insertions in advanced (high-grade) adenoma, a precancerous stage before colorectal carcinoma, suggests that the early and advanced polyp stages may host very important pathogenic processes concluding to cancer.

Multi-omic cross-sectional cohort study of pre-malignant Barrett’s esophagus reveals early structural variation and retrotransposon activity

“…Rather than the CNA or mutation burden, the SV landscape best describes the genomic variability across the cohort and, in keeping with this, there is an increasing number and complexity of rearrangements and LINE-1 retrotransposon events with advancing grade. Whilst these complex, large-scale rearrangements and retrotransposons are increasingly understood to have roles in multiple cancers, it has not been appreciated to this extent in pre-malignant disease, although LINE-1 retrotransposon activity has been demonstrated previously in very small numbers of pre-cancers, namely including benign BE 54 and colorectal adenomas 55,56 .…”

Value of methylation markers in colorectal cancer (Review)

“…LINEs are retrotransposable elements identified in numerous eukaryotic genomes. These are highly methylated in normal somatic cells and, therefore, are mostly inhibited, thus preventing their potential to cause genomic instability (78). Full-length LINE-1 can lead to adenoma formation and cancer progression, and the activity of LINE-1 is dependent on the epigenetic regulation of its promoter (79).…”

“…Jiang et al (81) examined promoter methylation of LINE-1 in adenomas and sessile serrated lesions (SSLS); the results showed that high-grade dysplasia (HGD) and increasing size of adenoma were associated with decreased LINE-1 methylation. Shademan et al (78) quantified promoter methylation and LINE-1 transcripts in three stages of CRC, non-advanced adenoma, advanced adenoma and adenocarcinoma. Their results demonstrated that the methylation of the LINE-1 promoter in non-advanced adenoma was significantly higher compared with that in advanced adenoma and adenocarcinoma.…”