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

Marta Kulis 1 Angelika Merkel 2 Simon Heath 2 Ana C. Queirós 1 Ronald P. Schuyler 3 Giancarlo Castellano 1 Renée Beekman 1 Emanuele Raineri 3 Anna Esteve 3 Guillem Clot 1 Néria Verdaguer-Dot 1 Martí Duran-Ferrer 2, 1 Nuria Russiñol 1 Roser Vilarrasa-Blasi 1 Simone Ecker 4 Vera Pancaldi 4 Daniel Rico 4 Lidia Agueda 2 Julie Blanc 2 David Richardson 5 Laura Clarke 5 Avik Datta 5 Marien Pascual 6 Xabier Agirre 6 Felipe Prosper 7, 6 Diego Alignani 6 Bruno Paiva 6, 7 Gersende Caron 8 Thierry Fest 8 Marcus O. Muench 9, 10 Marina E. Fomin 10, 9 Seung-Tae Lee 11 Joseph L. Wiemels 12 Alfonso Valencia 4 Marta Gut 2 Paul Flicek 5 Hendrik G. Stunnenberg 13 Reiner Siebert 14 Ralf Küppers 15 Ivo G. Gut 2 Elias Campo 1 José I Martín-Subero 1, *
Abstract : 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.
Keywords : Epigenomics
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Marta Kulis, Angelika Merkel, Simon Heath, Ana C. Queirós, Ronald P. Schuyler, et al.. Whole-genome fingerprint of the DNA methylome during human B cell differentiation. Nature Genetics, Nature Publishing Group, 2015, 47 (7), pp.746-756. ⟨10.1038/ng.3291⟩. ⟨hal-01163753⟩

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