title: Whole-genome fingerprint of the DNA methylome during human B cell differentiation.
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.
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Kulis
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Angelika
authors.initials: A
authors.lastname: Merkel
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Simon
authors.identifier: 0000000295500897
authors.initials: S
authors.lastname: Heath
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Queirós
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Ronald P
authors.identifier: 0000000160183935
authors.initials: RP
authors.lastname: Schuyler
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Renée
authors.initials: R
authors.lastname: Beekman
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Raineri
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Esteve
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Néria
authors.initials: N
authors.lastname: Verdaguer-Dot
authors.affiliation: 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.
authors.forename: Martí
authors.initials: M
authors.lastname: Duran-Ferrer
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Russiñol
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Vilarrasa-Blasi
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain.
authors.forename: Simone
authors.initials: S
authors.lastname: Ecker
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain.
authors.forename: Vera
authors.initials: V
authors.lastname: Pancaldi
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Agueda
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Julie
authors.initials: J
authors.lastname: Blanc
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: David
authors.identifier: 0000000302479118
authors.initials: D
authors.lastname: Richardson
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Laura
authors.identifier: 0000000259896898
authors.initials: L
authors.lastname: Clarke
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Avik
authors.identifier: 0000000214118638
authors.initials: A
authors.lastname: Datta
authors.affiliation: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Marien
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.affiliation: 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.
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.affiliation: Flow Cytometry Core, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Alignani
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Paiva
authors.affiliation: Université de Rennes 1, INSERM U917, Hematology Laboratory, University Hospital of Rennes, Rennes, France.
authors.forename: Gersende
authors.initials: G
authors.lastname: Caron
authors.affiliation: Université de Rennes 1, INSERM U917, Hematology Laboratory, University Hospital of Rennes, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.affiliation: 1] Blood Systems Research Institute, San Francisco, California, USA. [2] Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Marcus O
authors.identifier: 0000000189466605
authors.initials: MO
authors.lastname: Muench
authors.affiliation: 1] Blood Systems Research Institute, San Francisco, California, USA. [2] Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Fomin
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Molecular Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Institute of Human Genetics, Christian Albrechts University, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Elías
authors.identifier: 0000000198509793
authors.initials: E
authors.lastname: Campo
authors.affiliation: Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
mesh_terms: D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000276:immunology*; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics; D017422:Sequence Analysis, DNA