Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing

Jeong-Hyeon Choi, Yajun Li, Juyuan Guo, Lirong Pei, Tibor A. Rauch, Robin S. Kramer, Simone L. Macmil, Graham B. Wiley, Lynda B. Bennett, Jennifer L. Schnabel, Kristen H. Taylor, Sun Kim, Dong Xu, Arun Sreekumar, Gerd P. Pfeifer, Bruce A. Roe, Charles W. Caldwell, Kapil N. Bhalla, Huidong Shi

Research output: Contribution to journalArticle

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Abstract

Background: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) Bcells. 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.

Original languageEnglish (US)
Article numbere13020
JournalPloS one
Volume5
Issue number9
DOIs
StatePublished - Nov 1 2010

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bisulfites
Follicular Lymphoma
Methylation
DNA methylation
DNA Methylation
lymphoma
methylation
Genes
Genome
genome
Cells
B-lymphocytes
cells
B-Lymphocytes
Epigenomics
epigenetics
Histone Code
Histones
hydrogen sulfite
Carrier Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing. / Choi, Jeong-Hyeon; Li, Yajun; Guo, Juyuan; Pei, Lirong; Rauch, Tibor A.; Kramer, Robin S.; Macmil, Simone L.; Wiley, Graham B.; Bennett, Lynda B.; Schnabel, Jennifer L.; Taylor, Kristen H.; Kim, Sun; Xu, Dong; Sreekumar, Arun; Pfeifer, Gerd P.; Roe, Bruce A.; Caldwell, Charles W.; Bhalla, Kapil N.; Shi, Huidong.

In: PloS one, Vol. 5, No. 9, e13020, 01.11.2010.

Research output: Contribution to journalArticle

Choi, J-H, Li, Y, Guo, J, Pei, L, Rauch, TA, Kramer, RS, Macmil, SL, Wiley, GB, Bennett, LB, Schnabel, JL, Taylor, KH, Kim, S, Xu, D, Sreekumar, A, Pfeifer, GP, Roe, BA, Caldwell, CW, Bhalla, KN & Shi, H 2010, 'Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing', PloS one, vol. 5, no. 9, e13020. https://doi.org/10.1371/journal.pone.0013020
Choi, Jeong-Hyeon ; Li, Yajun ; Guo, Juyuan ; Pei, Lirong ; Rauch, Tibor A. ; Kramer, Robin S. ; Macmil, Simone L. ; Wiley, Graham B. ; Bennett, Lynda B. ; Schnabel, Jennifer L. ; Taylor, Kristen H. ; Kim, Sun ; Xu, Dong ; Sreekumar, Arun ; Pfeifer, Gerd P. ; Roe, Bruce A. ; Caldwell, Charles W. ; Bhalla, Kapil N. ; Shi, Huidong. / Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing. In: PloS one. 2010 ; Vol. 5, No. 9.
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abstract = "Background: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) Bcells. 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.",
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AU - Choi, Jeong-Hyeon

AU - Li, Yajun

AU - Guo, Juyuan

AU - Pei, Lirong

AU - Rauch, Tibor A.

AU - Kramer, Robin S.

AU - Macmil, Simone L.

AU - Wiley, Graham B.

AU - Bennett, Lynda B.

AU - Schnabel, Jennifer L.

AU - Taylor, Kristen H.

AU - Kim, Sun

AU - Xu, Dong

AU - Sreekumar, Arun

AU - Pfeifer, Gerd P.

AU - Roe, Bruce A.

AU - Caldwell, Charles W.

AU - Bhalla, Kapil N.

AU - Shi, Huidong

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