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

• DOI: 10.1038/ng.3291
• Publication Date: 2015-06-08T17:23:09Z
• Authors: Marta Kulis; Angelika Merkel; Simon Heath; Ana C Queirós; Ronald P Schuyler; Giancarlo Castellano; Renée Beekman; Emanuele Raineri; Anna Esteve; Guillem Clot; Néria Verdaguer-Dot; Martí Duran-Ferrer; Nuria Russiñol; Roser Vilarrasa-B...; Simone Ecker; Vera Pancaldi; Daniel Rico; Lidia Agueda; Julie Blanc; David Richardson; Laura Clarke; Avik Datta; Marien Pascual; Xabier Agirre; Felipe Prosper; Diego Alignani; Bruno Paiva; Gersende Caron; Thierry Fest; Marcus O Muench; Marina E Fomin; Seung-Tae Lee; Joseph L Wiemels; Alfonso Valencia; Marta Gut; Paul Flicek; Hendrik G Stunnen...; Reiner Siebert; Ralf Küppers; Ivo G Gut; Elías Campo; José I Martín-Subero
• Keywords: CpG site; Bisulfite sequencing; Methylated DNA immunoprecipitation; DNA demethylation; RNA-Directed DNA Methylation; Illumina Methylation Assay; Epigenomics

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.