Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation

Memory B cells (MBCs) have enhanced capabilities to differentiate to plasma cells and generate a rapid burst of antibodies upon secondary stimulation. To determine if MBCs harbor an epigenetic landscape that contributes to increased differentiation potential, we derived the chromatin accessibility and transcriptomes of influenza-specific IgM and IgG MBCs compared to naive cells. MBCs possessed an accessible chromatin architecture surrounding plasma cell specific genes, as well as altered expression of transcription factors and genes encoding cell cycle, chemotaxis, and signal transduction processes. Intriguingly, this MBC signature was conserved between humans and mice. MBCs of both species possessed a heightened heme signature compared to naive cells. Differentiation in the presence of hemin enhanced oxidative phosphorylation metabolism and MBC differentiation into antibody secreting plasma cells. Thus, these data define conserved MBC transcriptional and epigenetic signatures that include a central role for heme and multiple other pathways in augmenting MBC reactivation potential. Key PointsO_LIInfluenza-specific memory B cells have accessible chromatin structure. C_LIO_LIHuman and mouse memory B cells upregulate heme metabolic pathways. C_LIO_LIHeme enhances PC differentiation and augments mitochondrial metabolism in ex vivo. C_LI