Whole-genome fingerprint of the DNA methylome during human B cell differentiation
Kulis M(1), Merkel A(2), Heath S(2), Queirós AC(1), Schuyler RP(2), Castellano G(1), Beekman R(1), Raineri E(2), Esteve A(2), Clot G(1), Verdaguer-Dot N(1), Duran-Ferrer M(3), Russiñol N(1), Vilarrasa-Blasi R(1), Ecker S(4), Pancaldi V(4), Rico D(4), Agueda L(2), Blanc J(2), Richardson D(5), Clarke L(5), Datta A(5), Pascual M(6), Agirre X(6), Prosper F(7), Alignani D(8), Paiva B(9), Caron G(10), Fest T(10), Muench MO(11), Fomin ME(11), Lee ST(12), Wiemels JL(13), Valencia A(4), Gut M(2), Flicek P(5), Stunnenberg HG(14), Siebert R(15), Küppers R(16), Gut IG(2), Campo E(1), Martín-Subero JI(1).
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.