Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells

Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here, we use a multiparameter approach involving CD27 to segregate naive B cells (NBC), IgD(+) unswitched (unsw)MBCs and IgG(+) or IgA(+) class-switched (sw)MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG(+) and IgA(+) swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181, and concomitantly upregulated MIR181 target genes such as RASSF6, TOX, TRERF1, TRPV3 and ROR alpha, in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to the IgH chain locus on chromosome 14. Our findings thus provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease. Human memory B cells differentiate from naive B cells and can express different immunoglobulin (Ig) isotypes resulted from class-switch recombination. Here the authors describe, using transcriptional and epigenetic data from human memory B cells and integrated multi-omics analyses, the differentiation regulation and trajectory of IgG(+), IgA(+) and IgD(+) memory B cells.