Whole-genome fingerprint of the DNA methylome during human B cell differentiation
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-Blasi ; 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 Stunnenberg ; Reiner Siebert ; Ralf Küppers ; Ivo G Gut ; Elías Campo ; José I Martín-Subero
B-Lymphocytes/physiology* ; Base Sequence ; Cell Differentiation ; Cells, Cultured ; CpG Islands ; DNA Methylation* ; Epigenesis, Genetic/immunology* ; Gene Expression Regulation, Leukemic ; Genome, Human ; Humans ; Leukemia, B-Cell/genetics ; Sequence Analysis, DNA
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.