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Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia

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Item Type:Article
Title:Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia
Creators Name:Akalin, A. and Garrett-Bakelman, F.E. and Kormaksson, M. and Busuttil, J. and Zhang, L. and Khrebtukova, I. and Milne, T.A. and Huang, Y. and Biswas, D. and Hess, J.L. and Allis, C.D. and Roeder, R.G. and Valk, P.J.M. and Loewenberg, B. and Delwel, R. and Fernandez, H.F. and Paietta, E. and Tallman, M.S. and Schroth, G.P. and Mason, C.E. and Melnick, A. and Figueroa, M.E.
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.
Keywords:Acute Myeloid Leukemia, Base Sequence, CpG Islands, DNA Methylation, DNA Sequence Analysis, Genetic Epigenesis, Genetic Promoter Regions, HCT116 Cells, Human Genome, Isocitrate Dehydrogenase, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Neoplastic Gene Expression Regulation
Source:PLoS Genetics
Publisher:Public Library of Science
Page Range:e1002781
Date:21 June 2012
Official Publication:https://doi.org/10.1371/journal.pgen.1002781
PubMed:View item in PubMed

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