Whole-genome fingerprint of the DNA methylome during human B cell differentiation
Marta Kulis ; Angelika Merkel ; José I Martín-Subero ; Elías Campo ; Ivo G Gut ; Ralf Küppers ; Reiner Siebert ; Hendrik G Stunnenberg ; Paul Flicek ; Marta Gut ; Alfonso Valencia ; Joseph L Wiemels ; Seung-Tae Lee ; Marina E Fomin ; Marcus O Muench ; Thierry Fest ; Gersende Caron ; Bruno Paiva ; Diego Alignani ; Felipe Prosper ; Xabier Agirre ; Marien Pascual ; Avik Datta ; Laura Clarke ; David Richardson ; Julie Blanc ; Lidia Agueda ; Daniel Rico ; Vera Pancaldi ; Simone Ecker ; Roser Vilarrasa-Blasi ; Nuria Russiñol ; Martí Duran-Ferrer ; Néria Verdaguer-Dot ; Guillem Clot ; Anna Esteve ; Emanuele Raineri ; Renée Beekman ; Giancarlo Castellano ; Ronald P Schuyler ; Ana C Queirós ; Simon Heath
Nature Genetics, Vol.47(7) : 746~756, 2015
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.