Integrative analysis of human memory B cell coding and non-coding transcriptomes

Abstract

Abstract An effective response against previously experienced pathogens is contingent upon the unique functionality of memory B cells. These display intrinsic differences over naïve B cells, including longer lifespan and rapid response to antigen with production of high-affinity, class-switched antibodies. We have developed an integrated analysis of mRNA, miRNA and long non-coding RNA (lncRNA) profiles to determine how the mRNA transcriptome intersects with epigenetic regulatory non-coding RNAs to shape the functionality and phenotype of human memory B cells (CD27+IgG+ and CD27+IgA+) as compared to their naïve B cell counterparts (CD27−IgD+IgM+). Differential expression analysis revealed a novel gene signature shared by CD27+IgG+ and CD27+IgA+ cells, distinguishing memory from naïve B cells. Additionally, CD27+IgD+ B cells, which are not considered bona-fide memory, revealed a transcriptional identity straddling naïve and switched memory B cells. Signaling pathway analysis implicated the “memory” gene signature in the generation, homing and survival of class-switched memory B cells. Integrated analysis of mRNA and miRNA transcriptomes showed that in memory B cells the expression of select genes was dependent upon miRNA-mediated regulation. lncRNA analysis revealed that some of these RNAs clustered with IgH genes, thereby suggesting a role of such lncRNAs in the regulation of the IgH locus. Additional data suggested that select lncRNAs act as miRNA sponges. Thus, we have identified a novel set of genes that play a role in the generation and maintenance of memory B cells and have provided evidence that these genes are subjected to integrated regulation by distinct sets of miRNAs and lncRNAs.