| 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. © 2012 Akalin et al. |
| Keywords: |
controlled study; acute granulocytic leukemia; gene translocation; human cell; promoter region; sequence analysis; genetics; leukemia, myeloid, acute; molecular genetics; metabolism; gene expression profiling; bone marrow; hct116 cells; genetic variability; intron; gene function; dna methylation; gene expression regulation; oncogene; gene expression regulation, neoplastic; molecular sequence data; epigenetics; cpg island; cpg islands; epigenesis, genetic; promoter regions, genetic; human genome; nucleotide sequence; gene loss; base sequence; base pairing; dna sequence; cancer classification; genetic epigenesis; genome, human; cell strain hct116; transcription initiation site; sequence analysis, dna; isocitrate dehydrogenase; bisulfite; isocitrate dehydrogenase 1; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; mll protein, human; isocitrate dehydrogenase 2; idh1 protein, human; mixed lineage leukemia gene
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