Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth

Bo Zhao, James Zou, Hongfang Wang, Eric Johannsen, Chih Wen Peng, John Quackenbush, Jessica C. Mar, Cynthia Casson Morton, Matthew L. Freedman, Stephen C. Blacklow, Jon C. Aster, Bradley E. Bernstein, Elliott Kieff

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5′ of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.

Original languageEnglish (US)
Pages (from-to)14902-14907
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number36
DOIs
StatePublished - Sep 6 2011
Externally publishedYes

Fingerprint

Epstein-Barr Virus Nuclear Antigens
Human Herpesvirus 4
B-Lymphocytes
Growth
Nucleosomes
Cell Line
Chromatin
Transcription Factor RelA
Genome
Encyclopedias
DNA
Introns
Cluster Analysis

Keywords

  • Development
  • Leukemia
  • Lymphoma
  • Notch

ASJC Scopus subject areas

  • General

Cite this

Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. / Zhao, Bo; Zou, James; Wang, Hongfang; Johannsen, Eric; Peng, Chih Wen; Quackenbush, John; Mar, Jessica C.; Morton, Cynthia Casson; Freedman, Matthew L.; Blacklow, Stephen C.; Aster, Jon C.; Bernstein, Bradley E.; Kieff, Elliott.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 36, 06.09.2011, p. 14902-14907.

Research output: Contribution to journalArticle

Zhao, B, Zou, J, Wang, H, Johannsen, E, Peng, CW, Quackenbush, J, Mar, JC, Morton, CC, Freedman, ML, Blacklow, SC, Aster, JC, Bernstein, BE & Kieff, E 2011, 'Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 36, pp. 14902-14907. https://doi.org/10.1073/pnas.1108892108
Zhao, Bo ; Zou, James ; Wang, Hongfang ; Johannsen, Eric ; Peng, Chih Wen ; Quackenbush, John ; Mar, Jessica C. ; Morton, Cynthia Casson ; Freedman, Matthew L. ; Blacklow, Stephen C. ; Aster, Jon C. ; Bernstein, Bradley E. ; Kieff, Elliott. / Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 36. pp. 14902-14907.
@article{cb4e37eb73bf4e7e8e72b08bc015320b,
title = "Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth",
abstract = "Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78{\%}), early B-cell factor (EBF, 39{\%}), RUNX (43{\%}), ETS (39{\%}), NFκB (22{\%}), and PU.1 (22{\%}) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72{\%} RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54{\%}, 31{\%}, and 17{\%} of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14{\%} at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5′ of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.",
keywords = "Development, Leukemia, Lymphoma, Notch",
author = "Bo Zhao and James Zou and Hongfang Wang and Eric Johannsen and Peng, {Chih Wen} and John Quackenbush and Mar, {Jessica C.} and Morton, {Cynthia Casson} and Freedman, {Matthew L.} and Blacklow, {Stephen C.} and Aster, {Jon C.} and Bernstein, {Bradley E.} and Elliott Kieff",
year = "2011",
month = "9",
day = "6",
doi = "10.1073/pnas.1108892108",
language = "English (US)",
volume = "108",
pages = "14902--14907",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "36",

}

TY - JOUR

T1 - Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth

AU - Zhao, Bo

AU - Zou, James

AU - Wang, Hongfang

AU - Johannsen, Eric

AU - Peng, Chih Wen

AU - Quackenbush, John

AU - Mar, Jessica C.

AU - Morton, Cynthia Casson

AU - Freedman, Matthew L.

AU - Blacklow, Stephen C.

AU - Aster, Jon C.

AU - Bernstein, Bradley E.

AU - Kieff, Elliott

PY - 2011/9/6

Y1 - 2011/9/6

N2 - Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5′ of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.

AB - Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5′ of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.

KW - Development

KW - Leukemia

KW - Lymphoma

KW - Notch

UR - http://www.scopus.com/inward/record.url?scp=80052603592&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052603592&partnerID=8YFLogxK

U2 - 10.1073/pnas.1108892108

DO - 10.1073/pnas.1108892108

M3 - Article

C2 - 21746931

AN - SCOPUS:80052603592

VL - 108

SP - 14902

EP - 14907

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 36

ER -