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Genome-scale DNA methylation analysis identifies repeat element alterations that modulate the genomic stability of melanocytic nevi

ABSTRACT: Acquired melanocytic nevi grow and persist in a stable form into adulthood. Using genome-wide methylation profiling, we evaluated 32 histopathologically confirmed, and dermoscopically characterized nevi, with matched adjacent skin, to identify key epigenetic regulatory mechanisms involved in nevogenesis. Benign (n=13; 69% globular and 31% non-specific dermoscopic pattern) and dysplastic (n=19; 95% reticular/nonspecific dermoscopic pattern) nevi were dissimilar with only two shared differentially methylated (DM) loci. Relative to adjacent skin, benign nevi demonstrated an increase in both genome-scale methylation and methylation of Alu/LINE-1 retrotransposable elements, a marker of genomic stability, as well as global methylation. In contrast, dysplastic nevi showed evidence for genomic instability via hypomethylation of Alu/LINE-1. The difference in methylation between benign and dysplastic nevi was statistically significant for Alu (P = 0.00019) and LINE-1 (P = 0.000035) retrotransposable elements. Using dermoscopic classifications, reticular/nonspecific nevi had 59,572 CpG DM loci (Q < 0.05), whereas globular nevi had non-significant DM loci. The relative activity of reticular/non-specific nevi was evidenced by 50,720 hypomethylated loci being enriched for accessible chromatin, and 8,852 hypermethylated loci strongly enriched, for example, marks of active gene promoters, which suggests that gain of DNA methylation observed in these nevus types plays a role in gene regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188593 | GEO | 2021/12/07

REPOSITORIES: GEO

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Project description:Purpose: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. Methods: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38- or oxaliplatin-resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of DNA methylation entropy to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. Results: We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences -- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy. Investigation of the representive methylome of well-established SN38 and Oxaliplatin resistant cell line models and 14 clinical colorectal metastatic samples that have developed resistance to XELOX to review the epigenetic mechnism of the drug resistance.

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Genome-scale DNA methylation analysis identifies repeat element alterations that modulate the genomic stability of melanocytic nevi

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