title: Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells.
abstract: Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-?1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxy)methylation, and cell fate determination.
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Pôle de Biologie, Centre Hospitalier Universitaire (CHU), Rennes 35033, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Gersende
authors.initials: G
authors.lastname: Caron
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Mourad
authors.initials: M
authors.lastname: Hussein
authors.affiliation: Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Kulis
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Delaloy
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Pôle de Biologie, Centre Hospitalier Universitaire (CHU), Rennes 35033, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chatonnet
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Pignarre
authors.affiliation: Université de Rennes 1, Rennes 35065, France; Centre national de la recherche scientifique (CNRS), UMR6290, Rennes 35042, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Avner
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Lemarié
authors.affiliation: Université de Rennes 1, Rennes 35065, France; Centre national de la recherche scientifique (CNRS), UMR6290, Rennes 35042, France.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Mahé
authors.affiliation: Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Verdaguer-Dot
authors.affiliation: Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Queirós
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Pôle de Biologie, Centre Hospitalier Universitaire (CHU), Rennes 35033, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: Université de Rennes 1, Rennes 35065, France; Centre national de la recherche scientifique (CNRS), UMR6290, Rennes 35042, France. Electronic address: gilles.salbert@univ-rennes1.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salbert
authors.affiliation: INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Pôle de Biologie, Centre Hospitalier Universitaire (CHU), Rennes 35033, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France. Electronic address: thierry.fest@univ-rennes1.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
mesh_terms: D002453:Cell Cycle; D002478:Cells, Cultured; D019175:DNA Methylation; D006801:Humans; D038041:Lymphopoiesis; D010950:Plasma Cells / Q000166:cytology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D017455:Receptors, IgE; D012097:Repressor Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: 5hmC; B cell differentiation; DNA methylation; plasma cell differentiation; plasmablast