Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition

Virginia C. Rodríguez-Cortez, Lucia del Pino-Molina, Javier Rodríguez-Ubreva, Laura Ciudad, David Gómez-Cabrero, Carlos Company, José M. Urquiza, Jesper Tegnér, Carlos Rodríguez-Gallego, Eduardo López-Granados () and Esteban Ballestar ()
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Virginia C. Rodríguez-Cortez: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
Lucia del Pino-Molina: University Hospital La Paz
Javier Rodríguez-Ubreva: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
Laura Ciudad: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
David Gómez-Cabrero: Unit of Computational Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, L8:05
Carlos Company: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
José M. Urquiza: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
Jesper Tegnér: Unit of Computational Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, L8:05
Carlos Rodríguez-Gallego: University Hospital Son Espases, Carretera de Valldemossa, 79, 07120 Palma de Mallorca, Spain
Eduardo López-Granados: University Hospital La Paz
Esteban Ballestar: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals.

Date: 2015
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DOI: 10.1038/ncomms8335

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