Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia.
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.
Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America.
Altuna
A
Akalin
Francine E
FE
Garrett-Bakelman
Matthias
M
Kormaksson
Jennifer
J
Busuttil
Lu
L
Zhang
Irina
I
Khrebtukova
Thomas A
TA
Milne
Yongsheng
Y
Huang
Debabrata
D
Biswas
Jay L
JL
Hess
C David
CD
Allis
Robert G
RG
Roeder
Peter J M
PJ
Valk
Bob
B
Löwenberg
Ruud
R
Delwel
Hugo F
HF
Fernandez
Elisabeth
E
Paietta
Martin S
MS
Tallman
Gary P
GP
Schroth
Christopher E
CE
Mason
Ari
A
Melnick
Maria E
ME
Figueroa
D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA
C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D011495:Histone-Lysine N-Methyltransferase