DNA methylation on N(6)-adenine in mammalian embryonic stem cells

Nature. 2016 Apr 21;532(7599):329-33. doi: 10.1038/nature17640. Epub 2016 Mar 30.

Abstract

It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N(6)-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N(6)-methyladenine. An increase of N(6)-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N(6)-methyladenine deposition is inversely correlated with the evolutionary age of LINE-1 transposons; its deposition is strongly enriched at young (<1.5 million years old) but not old (>6 million years old) L1 elements. The deposition of N(6)-methyladenine correlates with epigenetic silencing of such LINE-1 transposons, together with their neighbouring enhancers and genes, thereby resisting the gene activation signals during embryonic stem cell differentiation. As young full-length LINE-1 transposons are strongly enriched on the X chromosome, genes located on the X chromosome are also silenced. Thus, N(6)-methyladenine developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. Our results demonstrate that N(6)-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / metabolism
  • AlkB Homolog 1, Histone H2a Dioxygenase
  • Animals
  • Cell Differentiation / genetics
  • DNA Methylation*
  • DNA Transposable Elements / genetics
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / deficiency
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic / genetics*
  • Evolution, Molecular
  • Gene Silencing
  • Long Interspersed Nucleotide Elements / genetics
  • Mammals / genetics
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Up-Regulation / genetics
  • X Chromosome / genetics
  • X Chromosome / metabolism

Substances

  • DNA Transposable Elements
  • AlkB Homolog 1, Histone H2a Dioxygenase
  • Alkbh1 protein, mouse
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • Adenine
  • 6-methyladenine