Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation

The epigenetic processes that regulate antibody secreting plasma cells are not well understood. Here, analysis of plasma cell differentiation revealed DNA hypomethylation of 10% of CpG loci that were overrepresented at enhancers. Inhibition of DNA methylation enhanced plasma cell commitment in a cell division-dependent manner. Examination of in vivo differentiating B cells stratified by cell division revealed a 5-fold increase in mRNA transcription coupled to DNA hypomethylation. Demethylation occurred first at binding motifs of NF-κB and AP-1 and later at those for IRF and Oct-2, and were coincident with activation and differentiation gene expression programs. These data provide mechanistic insight into the cell-division coupled transcriptional and epigenetic reprogramming and suggest DNA hypomethylation reflects the cis-regulatory history of plasma cell differentiation.