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Whole-genome fingerprint of the DNA methylome during human B cell differentiation

Autores: Kulis, M.; Merkel, A.; Heath, S.; Queiros, A. C.; Schuyler, R. P. ; Castellano, G.; Beekman, R.; Raineri, E.; Esteve, A.; Clot, G.; Verdaguer-Dot, N. ; Duran-Ferrer, M. ; Russinol, N.; Vilarrasa-Blasi, R.; Ecker, S.; Pancaldi, V. ; Rico, D.; Agueda, L.; Blanc, J.; Richardson, D. ; Clarke, L. ; Datta, A. ; Pascual De Pedro, Marién; Aguirre Ena, Xabier; Prosper Cardoso, Felipe; Alignani, Diego Oscar; Paiva, Bruno; Caron, G.; Fest, T.; Muench, M. O.; Fomin, M. E.; Lee, S. T. ; Wiemels, J. L. ; Valencia, A. ; Gut, M. ; Flicek, P. ; Stunnenberg, H. G.; Siebert, R.; Kuppers, R.; Gut, I. G. ; Campo, E. ; Martin-Subero, J. I.
Título de la revista: NATURE GENETICS
ISSN: 1061-4036
Volumen: 47
Número: 7
Páginas: 746 -56
Fecha de publicación: 2015
Resumen:
We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.
DOI: https://doi.org/10.1038/ng.3291
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