Research Paper

Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia

Volume 7, Issue 6   June 2012
Pages 567 - 578
http://dx.doi.org/10.4161/epi.20237
Keywords: DNA Methylation, NFATc1, chronic lymphocytic leukemia, next-generation sequencing, reduced representation bisulfite sequencing
Authors: Lirong Pei, Jeong-Hyeon Choi, Jimei Liu, Eun-Joon Lee, Brian McCarthy, James M. Wilson, Ethan Speir, Farrukh Awan, Hongseok Tae, Gerald Arthur, Jennifer L. Schnabel, Kristen H. Taylor, Xinguo Wang, Dong Xu, Han-Fei Ding, David H. Munn, Charles Caldwell and Huidong Shi

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Abstract:
We conducted a genome-wide DNA methylation analysis in CD19+ B-cells from chronic lymphocytic leukemia (CLL) patients and normal control samples using reduced representation bisulfite sequencing (RRBS). The methylation status of 1.8–2.3 million CpGs in the CLL genome was determined; about 45% of these CpGs were located in more than 23,000 CpG islands (CGIs). While global CpG methylation was similar between CLL and normal B-cells, 1764 gene promoters were identified as being differentially methylated in at least one CLL sample when compared with normal B-cell samples. Nineteen percent of the differentially methylated genes were involved in transcriptional regulation. Aberrant hypermethylation was found in all HOX gene clusters and a significant number of WNT signaling pathway genes. Hypomethylation occurred more frequently in the gene body including introns, exons, and 3′-UTRs in CLL. The NFATc1 P2 promoter and first intron was found to be hypomethylated and correlated with upregulation of both NFATc1 RNA and protein expression levels in CLL suggesting that an epigenetic mechanism is involved in the constitutive activation of NFAT activity in CLL cells. This comprehensive DNA methylation analysis will further our understanding of the epigenetic contribution to cellular dysfunction in CLL.

Received: February 25, 2012; Accepted: April 2, 2012; Published Online: June 1, 2012

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