The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion

Henar Hernando; Claire Shannon-Lowe; Abul B Islam; Fatima Al-Shahrour; Javier Rodríguez-Ubreva; Virginia C Rodríguez-Cortez; Biola M Javierre; Cristina Mangas; Agustín F Fernández; Maribel Parra; Henri-Jacques Delecluse; Manel Esteller; Eduardo López-Granados; Mario F Fraga; Nuria López-Bigas; Esteban Ballestar

doi:10.1186/gb-2013-14-1-r3

The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion

Henar Hernando, Claire Shannon-Lowe, Abul B Islam, Fatima Al-Shahrour, Javier Rodríguez-Ubreva, Virginia C Rodríguez-Cortez, Biola M Javierre, Cristina Mangas, Agustín F Fernández, Maribel Parra, Henri-Jacques Delecluse, Manel Esteller, Eduardo López-Granados, Mario F Fraga, Nuria López-Bigas, Esteban Ballestar

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

33 Citations (Scopus)

Abstract

BACKGROUND: Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.

RESULTS: We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.

CONCLUSIONS: Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.

Original language	English
Pages (from-to)	R3
Journal	Genome Biol
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/gb-2013-14-1-r3
Publication status	Published - 15 Jan 2013

Keywords

B-Lymphocytes
Cell Proliferation
DNA Methylation
Epstein-Barr Virus Infections
Gene Expression Profiling
Humans
Lymphocyte Activation
Transcription, Genetic
Up-Regulation
Journal Article
Research Support, Non-U.S. Gov't

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10.1186/gb-2013-14-1-r3

Molecular and Cellular Mechanisms of Synapse-Mediated Spread of Epstein Barr Virus: Overcoming the CD21-Restricted Cellular Tropism
Shannon-Lowe, C.
Medical Research Council
1/09/12 → 29/02/16
Project: Research Councils

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Hernando, H., Shannon-Lowe, C., Islam, A. B., Al-Shahrour, F., Rodríguez-Ubreva, J., Rodríguez-Cortez, V. C., Javierre, B. M., Mangas, C., Fernández, A. F., Parra, M., Delecluse, H-J., Esteller, M., López-Granados, E., Fraga, M. F., López-Bigas, N., & Ballestar, E. (2013). The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion. Genome Biol, 14(1), R3. https://doi.org/10.1186/gb-2013-14-1-r3

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title = "The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion",

abstract = "BACKGROUND: Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.RESULTS: We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.CONCLUSIONS: Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.",

keywords = "B-Lymphocytes, Cell Proliferation, DNA Methylation, Epstein-Barr Virus Infections, Gene Expression Profiling, Humans, Lymphocyte Activation, Transcription, Genetic, Up-Regulation, Journal Article, Research Support, Non-U.S. Gov't",

author = "Henar Hernando and Claire Shannon-Lowe and Islam, {Abul B} and Fatima Al-Shahrour and Javier Rodr{\'i}guez-Ubreva and Rodr{\'i}guez-Cortez, {Virginia C} and Javierre, {Biola M} and Cristina Mangas and Fern{\'a}ndez, {Agust{\'i}n F} and Maribel Parra and Henri-Jacques Delecluse and Manel Esteller and Eduardo L{\'o}pez-Granados and Fraga, {Mario F} and Nuria L{\'o}pez-Bigas and Esteban Ballestar",

year = "2013",

month = jan,

day = "15",

doi = "10.1186/gb-2013-14-1-r3",

language = "English",

volume = "14",

pages = "R3",

journal = "Genome Biol",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

}

Hernando, H, Shannon-Lowe, C, Islam, AB, Al-Shahrour, F, Rodríguez-Ubreva, J, Rodríguez-Cortez, VC, Javierre, BM, Mangas, C, Fernández, AF, Parra, M, Delecluse, H-J, Esteller, M, López-Granados, E, Fraga, MF, López-Bigas, N & Ballestar, E 2013, 'The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion', Genome Biol, vol. 14, no. 1, pp. R3. https://doi.org/10.1186/gb-2013-14-1-r3

TY - JOUR

T1 - The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion

AU - Hernando, Henar

AU - Shannon-Lowe, Claire

AU - Islam, Abul B

AU - Al-Shahrour, Fatima

AU - Rodríguez-Ubreva, Javier

AU - Rodríguez-Cortez, Virginia C

AU - Javierre, Biola M

AU - Mangas, Cristina

AU - Fernández, Agustín F

AU - Parra, Maribel

AU - Delecluse, Henri-Jacques

AU - Esteller, Manel

AU - López-Granados, Eduardo

AU - Fraga, Mario F

AU - López-Bigas, Nuria

AU - Ballestar, Esteban

PY - 2013/1/15

Y1 - 2013/1/15

N2 - BACKGROUND: Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.RESULTS: We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.CONCLUSIONS: Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.

AB - BACKGROUND: Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.RESULTS: We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.CONCLUSIONS: Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.

KW - B-Lymphocytes

KW - Cell Proliferation

KW - DNA Methylation

KW - Epstein-Barr Virus Infections

KW - Gene Expression Profiling

KW - Humans

KW - Lymphocyte Activation

KW - Transcription, Genetic

KW - Up-Regulation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1186/gb-2013-14-1-r3

DO - 10.1186/gb-2013-14-1-r3

M3 - Article

C2 - 23320978

SN - 1474-7596

VL - 14

SP - R3

JO - Genome Biol

JF - Genome Biol

IS - 1

ER -

The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion

Abstract

Keywords

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Molecular and Cellular Mechanisms of Synapse-Mediated Spread of Epstein Barr Virus: Overcoming the CD21-Restricted Cellular Tropism

Cite this