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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

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Authors

Natasha Vafadar-Isfahani

Christina Parr

Lara E. McMillan

Juliane Sanner

Zhao Yeo

Stephen Saddington

Oliver Peacock

Hazel A. Cruickshanks

Richard R. Meehan

JONATHAN LUND JON.LUND@NOTTINGHAM.AC.UK
Clinical Associate Professor

Cristina Tufarelli



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

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