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

Cancer Cell. 2019 Feb 11;35(2):297-314.e8. doi: 10.1016/j.ccell.2019.01.004.

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.

Keywords: 5-hydroxymethylation; BisChIP-seq; CpG islands; DNA methylation encroachment; H3K4 monomethylation; TAB-seq; WGBS; cancer; hypermethylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • 5-Methylcytosine / metabolism
  • Animals
  • Cell Line, Tumor
  • CpG Islands*
  • DNA Methylation*
  • DNA, Neoplasm / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Male
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Promoter Regions, Genetic

Substances

  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Histones
  • KMT2D protein, human
  • Neoplasm Proteins
  • 5-hydroxymethylcytosine
  • Myeloid-Lymphoid Leukemia Protein
  • 5-Methylcytosine
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse