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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).

(1) Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
(2) Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
(3) Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain. [2] Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
(4) Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain.
(5) European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
(6) Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
(7) [1] Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain. [2] Servicio de Hematología, Clínica Universidad de Navarra, Pamplona, Spain.
(8) Flow Cytometry Core, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
(9) [1] Servicio de Hematología, Clínica Universidad de Navarra, Pamplona, Spain. [2] Flow Cytometry Core, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
(10) Université de Rennes 1, INSERM U917, Hematology Laboratory, University Hospital of Rennes, Rennes, France.
(11) [1] Blood Systems Research Institute, San Francisco, California, USA. [2] Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
(12) Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
(13) Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
(14) Molecular Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.
(15) Institute of Human Genetics, Christian Albrechts University, Kiel, Germany.
(16) Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.

Revisão:Nature Genetics

Data: 8/Jun/2015

Área de Terapia Celular [ES]

Resumo

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.

CITAÇÃO DO ARTIGO  Nat Genet. 2015 Jun 8. doi: 10.1038/ng.3291.

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