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DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns


Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5' or 3' CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and commonly associates with gene suppression. We show that the pattern of H3K4me1 at CpG island borders in normal cells predicts the different modes of cancer CpG island hypermethylation. Notably, genetic manipulation of Kmt2d results in concordant alterations in H3K4me1 levels and CpG island border DNA methylation encroachment. Our findings suggest a role for H3K4me1 in the demarcation of CpG island methylation borders in normal cells, which become eroded in cancer.

Type Journal
ISBN 1878-3686 (Electronic) 1535-6108 (Linking)
Authors Skvortsova, K.; Masle-Farquhar, E.; Luu, P. L.; Song, J. Z.; Qu, W.; Zotenko, E.; Gould, C. M.; Du, Q.; Peters, T. J.; Colino-Sanguino, Y.; Pidsley, R.; Nair, S. S.; Khoury, A.; Smith, G. C.; Miosge, L. A.; Reed, J. H.; Kench, J. G.; Rubin, M. A.; Horvath, L.; Bogdanovic, O.; Lim, S. M.; Polo, J. M.; Goodnow, C. C.; Stirzaker, C.; Clark, S. J.
Responsible Garvan Author Prof Susan Clark
Publisher Name CANCER CELL
Published Date 2019-02-11
Published Volume 35
Published Issue 2
Published Pages 297-314 e8
Status Published in-print
DOI 10.1016/j.ccell.2019.01.004
URL link to publisher's version