Dnmt3a protects active chromosome domains against cancer-associated hypomethylation

PLoS Genet. 2012;8(12):e1003146. doi: 10.1371/journal.pgen.1003146. Epub 2012 Dec 20.

Abstract

Changes in genomic DNA methylation patterns are generally assumed to play an important role in the etiology of human cancers. The Dnmt3a enzyme is required for the establishment of normal methylation patterns, and mutations in Dnmt3a have been described in leukemias. Deletion of Dnmt3a in a K-ras-dependent mouse lung cancer model has been shown to promote tumor progression, which suggested that the enzyme might suppress tumor development by stabilizing DNA methylation patterns. We have used whole-genome bisulfite sequencing to comprehensively characterize the methylomes from Dnmt3a wildtype and Dnmt3a-deficient mouse lung tumors. Our results show that profound global methylation changes can occur in K-ras-induced lung cancer. Dnmt3a wild-type tumors were characterized by large hypomethylated domains that correspond to nuclear lamina-associated domains. In contrast, Dnmt3a-deficient tumors showed a uniformly hypomethylated genome. Further data analysis revealed that Dnmt3a is required for efficient maintenance methylation of active chromosome domains and that Dnmt3a-deficient tumors show moderate levels of gene deregulation in these domains. In summary, our results uncover conserved features of cancer methylomes and define the role of Dnmt3a in maintaining DNA methylation patterns in cancer.

Publication types

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

MeSH terms

  • Animals
  • Chromosomes / metabolism
  • DNA (Cytosine-5-)-Methyltransferases* / deficiency
  • DNA (Cytosine-5-)-Methyltransferases* / genetics
  • DNA (Cytosine-5-)-Methyltransferases* / metabolism
  • DNA Methylation*
  • Genome
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mutation
  • Neoplasms, Experimental* / genetics
  • Neoplasms, Experimental* / metabolism
  • Neoplasms, Experimental* / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • Proto-Oncogene Proteins p21(ras)