Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization

被引：101

作者：

Hansen, Kasper D. ^{[1
,2
,3
]}

Sabunciyan, Sarven ^{[2
,4
]}

Langmead, Ben ^{[2
,5
]}

Nagy, Noemi ^{[6
]}

Curley, Rebecca ^{[2
,7
]}

Klein, Georg ^{[6
]}

Klein, Eva ^{[6
]}

Salamon, Daniel ^{[6
]}

Feinberg, Andrew P. ^{[2
,7
]}

机构：

[1] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Ctr Epigenet, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21205 USA

[6] Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, S-17177 Stockholm, Sweden

[7] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA

来源：

GENOME RESEARCH | 2014年 / 24卷 / 02期

关键词：

LARGE GENE LISTS; EBV TRANSFORMATION; METHYLATED REGIONS; DNA METHYLATION; EXPRESSION; BIOINFORMATICS; ACTIVATION; LYMPHOMA; DOMAINS; GENOME;

D O I：

10.1101/gr.157743.113

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Altered DNA methylation occurs ubiquitously in human cancer from the earliest measurable stages. A cogent approach to understanding the mechanism and timing of altered DNA methylation is to analyze it in the context of carcinogenesis by a defined agent. Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma, but also used commonly in the laboratory to immortalize human B-cells in culture. Here we have performed whole-genome bisulfite sequencing of normal B-cells, activated B-cells, and EBV-immortalized B-cells from the same three individuals, in order to identify the impact of transformation on the methylome. Surprisingly, large-scale hypomethylated blocks comprising two-thirds of the genome were induced by EBV immortalization but not by B-cell activation per se. These regions largely corresponded to hypomethylated blocks that we have observed in human cancer, and they were associated with gene-expression hypervariability, similar to human cancer, and consistent with a model of epigenomic change promoting tumor cell heterogeneity. We also describe small-scale changes in DNA methylation near CpG islands. These results suggest that methylation disruption is an early and critical step in malignant transformation.

引用

页码：177 / 184

页数：8

共 46 条

[1] Methylome-wide comparison of human genomic DNA extracted from whole blood and from EBV-transformed lymphocyte cell lines [J].

Aberg, Karolina ;

Khachane, Amit N. ;

Rudolf, Gabor ;

Nerella, Srilaxmi ;

Fugman, Douglas A. ;

Tischfield, Jay A. ;

van den Oord, Edwin J. C. G. .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2012, 20 (09) :953-955

[2] Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains [J].

Berman, Benjamin P. ;

Weisenberger, Daniel J. ;

Aman, Joseph F. ;

Hinoue, Toshinori ;

Ramjan, Zachary ;

Liu, Yaping ;

Noushmehr, Houtan ;

Lange, Christopher P. E. ;

van Dijk, Cornelis M. ;

Tollenaar, Rob A. E. M. ;

Van den Berg, David ;

Laird, Peter W. .

NATURE GENETICS, 2012, 44 (01) :40-U62

[3] EPSTEIN-BARR-VIRUS (EBV) INDUCES EXPRESSION OF B-CELL ACTIVATION MARKERS ON INVITRO INFECTION OF EBV-NEGATIVE B-LYMPHOMA CELLS [J].

CALENDER, A ;

BILLAUD, M ;

AUBRY, JP ;

BANCHEREAU, J ;

VUILLAUME, M ;

LENOIR, GM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (22) :8060-8064

[4] The effects of EBV transformation on gene expression levels and methylation profiles [J].

Caliskan, Minal ;

Cusanovich, Darren A. ;

Ober, Carole ;

Gilad, Yoav .

HUMAN MOLECULAR GENETICS, 2011, 20 (08) :1643-1652

[5] Aberrations of EZH2 in Cancer [J].

Chase, Andrew ;

Cross, Nicholas C. P. .

CLINICAL CANCER RESEARCH, 2011, 17 (09) :2613-2618

[6] Genetic Analysis of Human Traits In Vitro: Drug Response and Gene Expression in Lymphoblastoid Cell Lines [J].

Choy, Edwin ;

Yelensky, Roman ;

Bonakdar, Sasha ;

Plenge, Robert M. ;

Saxena, Richa ;

De Jager, Philip L. ;

Shaw, Stanley Y. ;

Wolfish, Cara S. ;

Slavik, Jacqueline M. ;

Cotsapas, Chris ;

Rivas, Manuel ;

Dermitzakis, Emmanouil T. ;

Cahir-McFarland, Ellen ;

Kieff, Elliott ;

Hafler, David ;

Daly, Mark J. ;

Altshuler, David .

PLOS GENETICS, 2008, 4 (11)

[7] RAD21 Mutations Cause a Human Cohesinopathy [J].

Deardorff, Matthew A. ;

Wilde, Jonathan J. ;

Albrecht, Melanie ;

Dickinson, Emma ;

Tennstedt, Stephanie ;

Braunholz, Diana ;

Moennich, Maren ;

Yan, Yuqian ;

Xu, Weizhen ;

Concepcion Gil-Rodriguez, Maria ;

Clark, Dinah ;

Hakonarson, Hakon ;

Halbach, Sara ;

Michelis, Laura Daniela ;

Rampuria, Abhinav ;

Rossier, Eva ;

Spranger, Stephanie ;

Van Maldergem, Lionel ;

Lynch, Sally Ann ;

Gillessen-Kaesbach, Gabriele ;

Luedecke, Hermann-Josef ;

Ramsay, Robert G. ;

McKay, Michael J. ;

Krantz, Ian D. ;

Xu, Huiling ;

Horsfield, Julia A. ;

Kaiser, Frank J. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 90 (06) :1014-1027

[8] An integrated encyclopedia of DNA elements in the human genome [J].

Dunham, Ian ;

Kundaje, Anshul ;

Aldred, Shelley F. ;

Collins, Patrick J. ;

Davis, CarrieA. ;

Doyle, Francis ;

Epstein, Charles B. ;

Frietze, Seth ;

Harrow, Jennifer ;

Kaul, Rajinder ;

Khatun, Jainab ;

Lajoie, Bryan R. ;

Landt, Stephen G. ;

Lee, Bum-Kyu ;

Pauli, Florencia ;

Rosenbloom, Kate R. ;

Sabo, Peter ;

Safi, Alexias ;

Sanyal, Amartya ;

Shoresh, Noam ;

Simon, Jeremy M. ;

Song, Lingyun ;

Trinklein, Nathan D. ;

Altshuler, Robert C. ;

Birney, Ewan ;

Brown, James B. ;

Cheng, Chao ;

Djebali, Sarah ;

Dong, Xianjun ;

Dunham, Ian ;

Ernst, Jason ;

Furey, Terrence S. ;

Gerstein, Mark ;

Giardine, Belinda ;

Greven, Melissa ;

Hardison, Ross C. ;

Harris, Robert S. ;

Herrero, Javier ;

Hoffman, Michael M. ;

Iyer, Sowmya ;

Kellis, Manolis ;

Khatun, Jainab ;

Kheradpour, Pouya ;

Kundaje, Anshul ;

Lassmann, Timo ;

Li, Qunhua ;

Lin, Xinying ;

Marinov, Georgi K. ;

Merkel, Angelika ;

Mortazavi, Ali .

NATURE, 2012, 489 (7414) :57-74

[9] HYPOMETHYLATION DISTINGUISHES GENES OF SOME HUMAN CANCERS FROM THEIR NORMAL COUNTERPARTS [J].

FEINBERG, AP ;

VOGELSTEIN, B .

NATURE, 1983, 301 (5895) :89-92

[10] Bioconductor: open software development for computational biology and bioinformatics [J].

Gentleman, RC ;

Carey, VJ ;

Bates, DM ;

Bolstad, B ;

Dettling, M ;

Dudoit, S ;

Ellis, B ;

Gautier, L ;

Ge, YC ;

Gentry, J ;

Hornik, K ;

Hothorn, T ;

Huber, W ;

Iacus, S ;

Irizarry, R ;

Leisch, F ;

Li, C ;

Maechler, M ;

Rossini, AJ ;

Sawitzki, G ;

Smith, C ;

Smyth, G ;

Tierney, L ;

Yang, JYH ;

Zhang, JH .

GENOME BIOLOGY, 2004, 5 (10)

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