DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID

• Published in: Cell reports (Cambridge) 2015-09, Vol.12 (12), p.2086-2098
• Main Authors: Dominguez, Pilar M., Teater, Matt, Chambwe, Nyasha, Kormaksson, Matthias, Redmond, David, Ishii, Jennifer, Vuong, Bao, Chaudhuri, Jayanta, Melnick, Ari, Vasanthakumar, Aparna, Godley, Lucy A., Papavasiliou, F. Nina, Elemento, Olivier, Shaknovich, Rita
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell Differentiation; Cell Movement; Cell Proliferation; Conserved Sequence; Cytidine Deaminase - genetics; Cytidine Deaminase - immunology; Cytidine Deaminase - metabolism; Cytosine - metabolism; DNA Methylation; Epigenesis, Genetic; Germinal Center - cytology; Germinal Center - immunology; Germinal Center - metabolism; Humans; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.08.036

Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda−/−) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda−/− animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells. [Display omitted] •B cell transition through the GC is characterized by marked loss of DNA methylation•B cell transition through the GC is associated with increased methylome diversity•AID is essential for demethylation and diversification of methylome in GCBs•AID-dependent epigenetic hotspots are located in genes required for B cell function Dominguez et al. use mouse models to study changes in DNA methylation in B cells during entry into germinal centers in vivo. They determine that site-specific demethylation and diversification of methylome in germinal center B cells are dependent on AID function. AID-dependent epigenetic hotspots affect genes important for lymphocyte development.