Synthetic CpG islands reveal DNA sequence determinants of chromatin structure

Elife. 2014 Sep 26;3:e03397. doi: 10.7554/eLife.03397.

Abstract

The mammalian genome is punctuated by CpG islands (CGIs), which differ sharply from the bulk genome by being rich in G + C and the dinucleotide CpG. CGIs often include transcription initiation sites and display 'active' histone marks, notably histone H3 lysine 4 methylation. In embryonic stem cells (ESCs) some CGIs adopt a 'bivalent' chromatin state bearing simultaneous 'active' and 'inactive' chromatin marks. To determine whether CGI chromatin is developmentally programmed at specific genes or is imposed by shared features of CGI DNA, we integrated artificial CGI-like DNA sequences into the ESC genome. We found that bivalency is the default chromatin structure for CpG-rich, G + C-rich DNA. A high CpG density alone is not sufficient for this effect, as A + T-rich sequence settings invariably provoke de novo DNA methylation leading to loss of CGI signature chromatin. We conclude that both CpG-richness and G + C-richness are required for induction of signature chromatin structures at CGIs.

Keywords: CpG islands; DNA methylation; bivalent chromatin; chromosomes; genes; histone modifications; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AT Rich Sequence / genetics
  • Animals
  • Base Composition / genetics
  • Base Sequence
  • Cell Line
  • Chromatin / chemistry*
  • CpG Islands / genetics*
  • DNA Methylation
  • Embryonic Stem Cells / metabolism
  • Histones / metabolism
  • Lysine / metabolism
  • Mice
  • Promoter Regions, Genetic
  • RNA Polymerase II / metabolism
  • Trans-Activators / metabolism

Substances

  • Chromatin
  • Cxxc1 protein, mouse
  • Histones
  • Trans-Activators
  • RNA Polymerase II
  • Lysine