Induction of aberrant trimethylation of histone H3 lysine 27 by inflammation in mouse colonic epithelial cells

Carcinogenesis. 2012 Dec;33(12):2384-90. doi: 10.1093/carcin/bgs294. Epub 2012 Sep 13.


A field for cancerization (field defect), where genetic and epigenetic alterations are accumulated in normal-appearing tissues, is involved in human carcinogenesis, especially cancers associated with chronic inflammation. Although aberrant DNA methylation is involved in the field defect and induced by chronic inflammation, it is still unclear for trimethylation of histone H3 lysine 27 (H3K27me3), which is involved in gene repression independent of DNA methylation and functions as a pre-mark for aberrant DNA methylation. In this study, using a mouse colitis model induced by dextran sulfate sodium (DSS), we aimed to clarify whether aberrant H3K27me3 is induced by inflammation and involved in a field defect. ChIP-on-chip analysis of colonic epithelial cells revealed that H3K27me3 levels were increased or decreased for 266 genomic regions by aging, and more extensively (23 increased and 3574 decreased regions) by colitis. Such increase or decrease of H3K27me3 was induced as early as 2 weeks after the initiation of DSS treatment, and persisted at least for 16 weeks even after the inflammation disappeared. Some of the aberrant H3K27me3 in colonic epithelial cells was carried over into colon tumors. Furthermore, H3K27me3 acquired at Dapk1 by colitis was followed by increased DNA methylation, supporting its function as a pre-mark for aberrant DNA methylation. These results demonstrated that aberrant H3K27me3 can be induced by exposure to a specific environment, such as colitis, and suggested that aberrant histone modification, in addition to aberrant DNA methylation, is involved in the formation of a field defect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / physiology
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Colitis / genetics*
  • Colitis / pathology
  • Colon / metabolism*
  • Death-Associated Protein Kinases
  • Dextran Sulfate
  • Epithelial Cells / pathology*
  • Gene Expression
  • Histones / chemistry
  • Histones / metabolism*
  • Intestinal Mucosa / pathology
  • Lysine / metabolism*
  • Male
  • Methylation
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / metabolism
  • Neoplasms / pathology


  • Apoptosis Regulatory Proteins
  • Histones
  • Dextran Sulfate
  • DAPK1 protein, human
  • Dapk1 protein, mouse
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Lysine