Base-pair Resolution DNA Methylation Sequencing Reveals Profoundly Divergent Epigenetic Landscapes in Acute Myeloid Leukemia

PLoS Genet. 2012;8(6):e1002781. doi: 10.1371/journal.pgen.1002781. Epub 2012 Jun 21.

Abstract

We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions.

Publication types

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

MeSH terms

  • Base Sequence
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Genome, Human
  • HCT116 Cells
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Leukemia, Myeloid, Acute / genetics*
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Promoter Regions, Genetic
  • Sequence Analysis, DNA

Substances

  • KMT2A protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Histone-Lysine N-Methyltransferase