Decoupling of DNA methylation and activity of intergenic LINE-1 promoters in colorectal cancer.
journal contributionposted on 2019-07-03, 13:58 authored by N Vafadar-Isfahani, C Parr, LE McMillan, J Sanner, Z Yeo, S Saddington, O Peacock, HA Cruickshanks, RR Meehan, JN Lund, C Tufarelli
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.
Research was supported by the Derby Teaching Hospitals NHS Foundation Trust Colorectal Cancer Charitable Fund; and by Genetic Society summer scholarships to LMM and CP. NV-I was supported by a University Research Scholarship Doctoral Training Award from the University of Nottingham. Research in RRM laboratory is supported by the MRC.
CitationEpigenetics, 2017, 12 (6), pp. 465-475
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre
- VoR (Version of Record)
PublisherTaylor & Francis for Epigenetics Society
CRCH4K20me3L1-ASPL1PA2LCTLINE-1chromatincolorectal cancermethylationretrotransposonsAzacitidineColorectal NeoplasmsDNA (Cytosine-5-)-Methyltransferase 1DNA (Cytosine-5-)-MethyltransferasesDNA MethylationGene Expression Regulation, NeoplasticHCT116 CellsHumansLong Interspersed Nucleotide ElementsPromoter Regions, Genetic