Abstract
Methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP-seq) has the potential to identify changes in DNA methylation important in cancer development. In order to understand the role of epigenetic modulation in the development of acute myeloid leukemia (AML) we have applied MeDIP-seq to the DNA of 12 AML patients and 4 normal bone marrows. This analysis revealed leukemia-associated differentially methylated regions that included gene promoters, gene bodies, CpG islands and CpG island shores. Two genes (SPHKAP and DPP6) with significantly methylated promoters were of interest and further analysis of their expression showed them to be repressed in AML. We also demonstrated considerable cytogenetic subtype specificity in the methylomes affecting different genomic features. Significantly distinct patterns of hypomethylation of certain interspersed repeat elements were associated with cytogenetic subtypes. The methylation patterns of members of the SINE family tightly clustered all leukemic patients with an enrichment of Alu repeats with a high CpG density (P<0.0001). We were able to demonstrate significant inverse correlation between intragenic interspersed repeat sequence methylation and gene expression with SINEs showing the strongest inverse correlation (R2 = 0.7). We conclude that the alterations in DNA methylation that accompany the development of AML affect not only the promoters, but also the non-promoter genomic features, with significant demethylation of certain interspersed repeat DNA elements being associated with AML cytogenetic subtypes. MeDIP-seq data were validated using bisulfite pyrosequencing and the Infinium array.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous form of cancer in which many molecular and cytogenetic somatically acquired events have been described [1]
For interpretation of DNA methylation signals, we used the Batman algorithm [11,12], which takes into account the underlying CpG density to obtain quantification of methylation
AML and its subtypes we investigated whether methylation of specific genomic features could discriminate between AML and normal bone marrows (NBMs)
Summary
Acute myeloid leukemia (AML) is a heterogeneous form of cancer in which many molecular and cytogenetic somatically acquired events have been described [1]. These somatic changes have considerable influence over clinical outcome and constitute valuable biomarkers for disease classification [2] their role in the evolution of the stem cell to a fully transformed leukemic cell has yet to be completely understood. The MLL gene is involved in many chromosomal translocations in leukemia [3] and can be altered by partial tandem duplication This gene is recognized as a histone methyltransferase. In order to fully understand the role of DNA methylation in AML, a global view of the AML methylome is required
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