Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells

Gersende Caron (1, 2, 3) , Mourad Hussein (3, 2) , Marta Kulis (4) , Céline Delaloy (5, 3) , Fabrice Chatonnet (3, 1, 2) , Amandine Pignarre (3, 2) , Stéphane Avner (6) , Maud Lemarié (3, 2) , Elise A. Mahé (6) , Nuria Verdaguer-Dot (4) , Ana C. Queiros (4) , Karin Tarte (3, 1, 2) , José I. Martin-Subero (4) , Gilles Salbert (6) , Thierry Fest (3, 1, 2)

1 Pôle biologie
2 EFS Bretagne - Etablissement français du sang [Rennes]
3 MiCa - Microenvironnement et cancer
4 UB - Universitat de Barcelona
5 Etablissement Français du Sang Bretagne
6 IGDR - Institut de Génétique et Développement de Rennes

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 TGF­β1/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.

Keywords: plasmablast; 5hmC; B cell differentiation; DNA methylation; plasma cell differentiation

Domains: Life Sciences [q-bio]; Cancer

Gersende Caron, Mourad Hussein, Marta Kulis, Céline Delaloy, Fabrice Chatonnet, et al.. Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells. Cell Reports, 2015, 13 (5), pp.1059-1071. ⟨10.1016/j.celrep.2015.09.051⟩. ⟨hal-01219671⟩