title: NF-κB directly mediates epigenetic deregulation of common microRNAs in Epstein-Barr virus-mediated transformation of B-cells and in lymphomas.
abstract: MicroRNAs (miRNAs) have negative effects on gene expression and are major players in cell function in normal and pathological conditions. Epstein-Barr virus (EBV) infection of resting B lymphocytes results in their growth transformation and associates with different B cell lymphomas. EBV-mediated B cell transformation involves large changes in gene expression, including cellular miRNAs. We performed miRNA expression analysis in growth transformation of EBV-infected B cells. We observed predominant downregulation of miRNAs and upregulation of a few miRNAs. We observed similar profiles of miRNA expression in B cells stimulated with CD40L/IL-4, and those infected with EBNA-2- and LMP-1-deficient EBV particles, suggesting the implication of the NF-kB pathway, common to all four situations. In fact, the NF-kB subunit p65 associates with the transcription start site (TSS) of both upregulated and downregulated miRNAs following EBV infection This occurs together with changes at histone H3K27me3 and histone H3K4me3. Inhibition of the NF-kB pathway impairs changes in miRNA expression, NF-kB binding and changes at the above histone modifications near the TSS of these miRNA genes. Changes in expression of these miRNAs also occurred in diffuse large B cell lymphomas (DLBCL), which are strongly NF-kB dependent. Our results highlight the relevance of the NF-kB pathway in epigenetically mediated miRNA control in B cell transformation and DLBCL.
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Vento-Tormo
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Ubreva
authors.affiliation: Pathology Department, Hospital Universitario Marques de Valdecilla, Cancer Genomics, IFIMAV, 39008 Santander, Spain.
authors.forename: Lorena Di
authors.initials: LD
authors.lastname: Lisio
authors.affiliation: Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Urquiza
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Henar
authors.initials: H
authors.lastname: Hernando
authors.affiliation: Department of Experimental and Health Sciences, Barcelona Biomedical Research Park, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain Catalan Institution for Research and Advanced Studies (ICREA), 08003 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: López-Bigas
authors.affiliation: CR-UK Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Shannon-Lowe
authors.affiliation: Pathology Department, Hospital Universitario Marques de Valdecilla, Cancer Genomics, IFIMAV, 39008 Santander, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Martínez
authors.affiliation: Pathology Department, Hospital Universitario Marques de Valdecilla, Cancer Genomics, IFIMAV, 39008 Santander, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Montes-Moreno
authors.affiliation: Pathology Department, Hospital Universitario Marques de Valdecilla, Cancer Genomics, IFIMAV, 39008 Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain eballestar@idibell.cat.
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B