G9a controls plasma cell differentiation through FOXO1 and ETS1 binding site regulatory networks.

B cell differentiation is tightly regulated through coordinated changes in metabolism, division, expression of transcription factors, and epigenetic programming mediated by histone modifying enzymes. Here, we examined the role of an epigenetic writer, the histone H3K9 mono and dimethyltransferase G9a, in B cell development and plasma cell (PC) formation in vivo. Utilizing a B cell specific G9afl/flCd19Cre/+ conditional mouse model we found a significant decrease of marginal zone B cells in G9a knockout (KO) mice. When challenged with a T cell-independent antigen LPS, these mice displayed increased frequencies of activated B cells and plasma cells. Compared to control mice, G9a KO activated B cells divided fewer times before expressing the plasma cell marker CD138. RNA-seq and ATAC-seq revealed dysregulation of genes involved in regulating proliferation and PC function. Integrated bioinformatics analyses identified potential transcription factor targets of G9a as FOXO1, ETS1, and ELF1 as their putative target genes were dysregulated, thereby providing a potential mechanism for how these pathways are controlled. Importantly G9a deficiency was associated with genes that were both up and down modulated, highlighting distinct regulatory modes of action. Together, these data show that G9a is critical to the fate and restricts specific aspects of plasma cell formation, providing a unique set of target genes that could be manipulated in therapies aimed at controlling B cell and PC function or formation.