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

Ksenia Skvortsova, Etienne Masle-Farquhar, Phuc Loi Luu, Jenny Z. Song, Wenjia Qu, Elena Zotenko, Cathryn M. Gould, Qian Du, Timothy J. Peters, Yolanda Colino-Sanguino, Ruth Pidsley, Shalima S. Nair, Amanda Khoury, Grady C. Smith, Lisa A. Miosge, Joanne H. Reed, James G. Kench, Mark A. Rubin, Lisa Horvath, Ozren BogdanovicSue Mei Lim, Jose M. Polo, Christopher C. Goodnow, Clare Stirzaker, Susan J. Clark

Research output: Contribution to journalArticleResearchpeer-review

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)297-314
Number of pages18
JournalCancer Cell
Volume35
Issue number2
DOIs
Publication statusPublished - 11 Feb 2019

Keywords

  • 5-hydroxymethylation
  • BisChIP-seq
  • cancer
  • CpG islands
  • DNA methylation encroachment
  • H3K4 monomethylation
  • hypermethylation
  • TAB-seq
  • WGBS

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