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

Hernando, Henar; Shannon Lowe, Claire; Islam, Abul, 1978-; Al-Shahrour, Fátima; Rodríguez Ubreva, Javier; Rodríguez Cortez, Virginia C; Javierre, Biola M.; Mangas, Cristina; Fernández, Agustín F.; Parra, Maribel; Delecluse, Henri Jacques; Esteller, Manel; López Granados, Eduardo; Fraga, Mario F.; López Bigas, Núria; Ballestar, Esteban

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

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dc.contributor.author Hernando, Henarca
dc.contributor.author Shannon Lowe, Claireca
dc.contributor.author Islam, Abul, 1978-ca
dc.contributor.author Al-Shahrour, Fátimaca
dc.contributor.author Rodríguez Ubreva, Javierca
dc.contributor.author Rodríguez Cortez, Virginia Cca
dc.contributor.author Javierre, Biola M.ca
dc.contributor.author Mangas, Cristinaca
dc.contributor.author Fernández, Agustín F.ca
dc.contributor.author Parra, Maribelca
dc.contributor.author Delecluse, Henri Jacquesca
dc.contributor.author Esteller, Manelca
dc.contributor.author López Granados, Eduardoca
dc.contributor.author Fraga, Mario F.ca
dc.contributor.author López Bigas, Núriaca
dc.contributor.author Ballestar, Estebanca
dc.date.accessioned 2015-03-16T08:16:11Z
dc.date.available 2015-03-16T08:16:11Z
dc.date.issued 2013ca
dc.description.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.en
dc.description.sponsorship This work was supported by grants PI081346 (FIS) and SAF2011-29635 from the Spanish Ministry of Science and Innovation (MICINN) and grant 2009SGR184 from AGAUR (Catalan Government). AI was supported by fellowship from AGAUR, Government of Catalonia, Spain. MP is supported by Ramon y Cajal Programmeen
dc.format.mimetype application/pdfca
dc.identifier.citation 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 HJ, Esteller M, López-Granados E, Fraga MF, López-Bigas N, Ballestar E. The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion. Genome Biology. 2013; 14: R3. DOI 10.1186/gb-2013-14-1-r3ca
dc.identifier.doi http://dx.doi.org/10.1186/gb-2013-14-1-r3
dc.identifier.issn 1465-6906ca
dc.identifier.uri http://hdl.handle.net/10230/23183
dc.language.iso engca
dc.publisher BioMed Centralca
dc.relation.ispartof Genome Biology. 2013; 14: R3
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29635
dc.rights © 2013 Hernando et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/2.0
dc.subject.other Cèl·lules Bca
dc.subject.other Virus d'Epstein-Barrca
dc.title The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversionen
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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