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)

1 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
2 CNAG - Centro Nacional de Análisi Genómico
3 Centre for Epidemiological Studies on HIV/AIDS and STI of Catalonia (CEEISCAT)
4 CNIO - Spanish National Cancer Research Center
5 EMBL-EBI - European Bioinformatics Institute [Hinxton]
6 CIMA - Center for Applied Medical Research [Plamplona]
7 UNIVERSIDAD DE NAVARRA - Clinica Universitaria, faculdad de medicina ; universidad de Navarra
8 MiCa - Microenvironnement et cancer
9 Department of Laboratory Medicine [San Francisco]
10 Blood Systems Research Institute
11 Yonsei University College of Medicine
12 Department of Epidemiology and Biostatistics
13 Department of Molecular Biology [Nijmegen]
14 Institute of Human Genetics
15 Institute of Cell Biology, IFZ

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

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Genetics

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, 2015, 47 (7), pp.746-756. ⟨10.1038/ng.3291⟩. ⟨hal-01163753⟩