Genome-Wide DNA Methylation Maps in Follicular Lymphoma Cells Determined by Methylation-Enriched Bisulfite Sequencing
Rauch, Tibor A.
Kramer, Robin S.
Macmil, Simone L.
Wiley, Graham B.
Bennett, Lynda B.
Schnabel, Jennifer L.
Taylor, Kristen H.
Pfeifer, Gerd P.
Roe, Bruce A.
Caldwell, Charles W.
Bhalla, Kapil N.
MetadataShow full item record
AbstractBackground: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL.
Methodology/Principal Findings: We performed methylation-enriched genome-wide bisulfite sequencing of FL cells and normal CD19+ B-cells using 454 sequencing technology. The methylated DNA fragments were enriched with methyl-binding proteins, treated with bisulfite, and sequenced using the Roche-454 GS FLX sequencer. The total number of bases covered in the human genome was 18.2 and 49.3 million including 726,003 and 1.3 million CpGs in FL and CD19+ B-cells, respectively. 11,971 and 7,882 methylated regions of interest (MRIs) were identified respectively. The genome-wide distribution of these MRIs displayed significant differences between FL and normal B-cells. A reverse trend in the distribution of MRIs between the promoter and the gene body was observed in FL and CD19+ B-cells. The MRIs identified in FL cells also correlated well with transcriptomic data and ChIP-on-Chip analyses of genome-wide histone modifications such as tri-methyl-H3K27, and tri-methyl-H3K4, indicating a concerted epigenetic alteration in FL cells.
Conclusions/Significance: This study is the first to provide a large scale and comprehensive analysis of the DNA methylation sequence composition and distribution in the FL epigenome. These integrated approaches have led to the discovery of novel and frequent targets of aberrant epigenetic alterations. The genome-wide bisulfite sequencing approach developed here can be a useful tool for profiling DNA methylation in clinical samples.
CitationPLoS One. 2010 Sep 29; 5(9):e13020
- Ultradeep bisulfite sequencing analysis of DNA methylation patterns in multiple gene promoters by 454 sequencing.
- Authors: Taylor KH, Kramer RS, Davis JW, Guo J, Duff DJ, Xu D, Caldwell CW, Shi H
- Issue date: 2007 Sep 15
- Bisulfite Patch PCR enables multiplexed sequencing of promoter methylation across cancer samples.
- Authors: Varley KE, Mitra RD
- Issue date: 2010 Sep
- Analyzing the cancer methylome through targeted bisulfite sequencing.
- Authors: Lee EJ, Luo J, Wilson JM, Shi H
- Issue date: 2013 Nov 1
- DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control.
- Authors: Kretzmer H, Bernhart SH, Wang W, Haake A, Weniger MA, Bergmann AK, Betts MJ, Carrillo-de-Santa-Pau E, Doose G, Gutwein J, Richter J, Hovestadt V, Huang B, Rico D, Jühling F, Kolarova J, Lu Q, Otto C, Wagener R, Arnolds J, Burkhardt B, Claviez A, Drexler HG, Eberth S, Eils R, Flicek P, Haas S, Humme M, Karsch D, Kerstens HHD, Klapper W, Kreuz M, Lawerenz C, Lenzek D, Loeffler M, López C, MacLeod RAF, Martens JHA, Kulis M, Martín-Subero JI, Möller P, Nage I, Picelli S, Vater I, Rohde M, Rosenstiel P, Rosolowski M, Russell RB, Schilhabel M, Schlesner M, Stadler PF, Szczepanowski M, Trümper L, Stunnenberg HG, Küppers R, Ammerpohl O, Lichter P, Siebert R, Hoffmann S, Radlwimmer B
- Issue date: 2015 Nov
- High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing.
- Authors: Hodges E, Smith AD, Kendall J, Xuan Z, Ravi K, Rooks M, Zhang MQ, Ye K, Bhattacharjee A, Brizuela L, McCombie WR, Wigler M, Hannon GJ, Hicks JB
- Issue date: 2009 Sep