Whole-genome fingerprint of the DNA methylome during human B cell differentiation.
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.
Kulis, M; Merkel, A; Heath, S; Queirós, AC; Schuyler, RP; Castellano, G; Beekman, R; Raineri, E; Esteve, A; Clot, G; Verdaguer-Dot, N; Duran-Ferrer, M; Russiñol, N; Vilarrasa-Blasi, R; Ecker, S; Pancaldi, V; Rico, D; Agueda, L; Blanc, J; Richardson, D; Clarke, L; Datta, A; Pascual, M; Agirre, X; Prosper, F; Alignani, D; Paiva, B; Caron, G; Fest, T; Muench, MO; Fomin, ME; Lee, S-T; Wiemels, JL; Valencia, A; Gut, M; Flicek, P; Stunnenberg, HG; Siebert, R; Küppers, R; Gut, IG; Campo, E et al.
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