Large conserved domains of low DNA methylation maintained by Dnmt3a

Nat Genet. 2014 Jan;46(1):17-23. doi: 10.1038/ng.2836. Epub 2013 Nov 24.

Abstract

Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

Publication types

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

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Animals
  • Base Sequence
  • Conserved Sequence
  • CpG Islands
  • Cytosine / analogs & derivatives
  • Cytosine / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation*
  • Databases, Genetic
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Hematopoietic Stem Cells / physiology
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Leukemia / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains

Substances

  • Histones
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A

Associated data

  • GEO/GSE49191