Decoupling of DNA methylation and activity of intergenic LINE-1 promoters in colorectal cancer

Vafadar-Isfahani, Natasha; Parr, Christina; McMillan, Lara E.; Sanner, Juliane; Yeo, Zhao; Saddington, Stephen; Peacock, Oliver; Cruickshanks, Hazel A.; Meehan, Richard R.; Lund, Jonathan N.; Tufarelli, Cristina

Abstract

Hypomethylation of LINE-1 repeats in cancer has been proposed as the main mechanism behind their activation; this assumption, however, was based on findings from early studies that were biased toward young and transpositionally active elements. Here, we investigate the relationship between methylation of 2 intergenic, transpositionally inactive LINE-1 elements and expression of the LINE-1 chimeric transcript (LCT) 13 and LCT14 driven by their antisense promoters (L1-ASP). Our data from DNA modification, expression, and 5'RACE analyses suggest that colorectal cancer methylation in the regions analyzed is not always associated with LCT repression. Consistent with this, in HCT116 colorectal cancer cells lacking DNA methyltransferases DNMT1 or DNMT3B, LCT13 expression decreases, while cells lacking both DNMTs or treated with the DNMT inhibitor 5-azacytidine (5-aza) show no change in LCT13 expression. Interestingly, levels of the H4K20me3 histone modification are inversely associated with LCT13 and LCT14 expression. Moreover, at these LINE-1s, H4K20me3 levels rather than DNA methylation seem to be good predictor of their sensitivity to 5-aza treatment. Therefore, by studying individual LINE-1 promoters we have shown that in some cases these promoters can be active without losing methylation; in addition, we provide evidence that other factors (e.g., H4K20me3 levels) play prominent roles in their regulation.

Citation

Vafadar-Isfahani, N., Parr, C., McMillan, L. E., Sanner, J., Yeo, Z., Saddington, S., …Tufarelli, C. (2017). Decoupling of DNA methylation and activity of intergenic LINE-1 promoters in colorectal cancer. Epigenetics, 12(6), 465-475. https://doi.org/10.1080/15592294.2017.1300729

• Journal Article Type: Article
• Acceptance Date: Mar 16, 2018
• Online Publication Date: Apr 12, 2017
• Publication Date: Jun 3, 2017
• Deposit Date: Jun 10, 2019
• Publicly Available Date: Jun 25, 2019
• Journal: Epigenetics
• Print ISSN: 1559-2294
• Electronic ISSN: 1559-2308
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 6
• Pages: 465-475
• DOI: https://doi.org/10.1080/15592294.2017.1300729
• Keywords: CRC, chromatin, colorectal cancer, H4K20me3, L1PA2, LINE-1, LCT, L1-ASP, methylation, retrotransposons
• Public URL: https://nottingham-repository.worktribe.com/output/1379581
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/15592294.2017.1300729
• Additional Information: Peer Review Statement: The publishing and review policy for this title is described in its Aims & Scope.; Aim & Scope: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=kepi20