Regional activation of the cancer genome by long-range epigenetic remodeling

Cancer Cell. 2013 Jan 14;23(1):9-22. doi: 10.1016/j.ccr.2012.11.006. Epub 2012 Dec 13.

Abstract

Epigenetic gene deregulation in cancer commonly occurs through chromatin repression and promoter hypermethylation of tumor-associated genes. However, the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood. Here, we identify a mechanism of domain gene deregulation through coordinated long-range epigenetic activation (LREA) of regions that typically span 1 Mb and harbor key oncogenes, microRNAs, and cancer biomarker genes. Gene promoters within LREA domains are characterized by a gain of active chromatin marks and a loss of repressive marks. Notably, although promoter hypomethylation is uncommon, we show that extensive DNA hypermethylation of CpG islands or "CpG-island borders" is strongly related to cancer-specific gene activation or differential promoter usage. These findings have wide ramifications for cancer diagnosis, progression, and epigenetic-based gene therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Genome*
  • Histones / metabolism
  • Humans
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / physiology
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics*

Substances

  • Histones
  • MicroRNAs

Associated data

  • GEO/GSE24546
  • GEO/GSE38685