BRWD1 establishes germinal center B cell epigenetic states to prevent apoptosis and inflammation

Abstract Germinal centers (GCs) drive adaptive humoral immunity by selecting for B cells with high affinity antibodies and producing memory B cells and plasma cells. We previously defined three GC B cell subpopulations that are undergoing either selection, proliferation, or somatic hypermutation with distinct transcriptional and chromatin accessibility profiles. We hypothesized that the epigenetic reader BRWD1, which regulates chromatin accessibility during B cell lymphopoiesis, also regulates the chromatin accessibility and differentiation of GC B cells. To study the role of BRWD1 in GC B cells, we generated Aicda cre× Brwd1 fl/flmice and performed ATAC-seq to measure chromatin accessibility. Loss of Brwd1 caused an epigenetic collapse whereby differential chromatin accessibility between GC B cell subpopulations was lost. This was accompanied by SPIB and PU.1 binding motifs becoming more accessible among GC B cell subpopulations. Functionally, loss of Brwd1 promoted proliferation, and GC structures were larger and more frequent. However, the rate of somatic hypermutation was unaltered. Interestingly, Brwd1-deficient GCs had massive apoptotic debris by histology, which was consistent with strong inflammatory and apoptosis transcriptional signatures measured by RNA-seq. Finally, Brwd1 deletion caused a decrease in pre-memory B cell differentiation, and resultant plasma cells had decreased immunoglobulin mutations. We conclude that BRWD1 regulates chromatin accessibility to compartmentalize the molecular functions of each GC B cell subpopulation and to prevent apoptosis-induced inflammation. This research was funded by grants R01 AI143778 and F30 AI174324 from the NIH/NIAID.