BRWD1 directs B cell epigenetic states required for germinal center initiation, maintenance and function

Germinal center (GC) B cells, differentiated from follicular B cells following activation, can be assigned to light zone (LZ), dark zone proliferation (DZp), or dark zone differentiation (DZd) states, as compartmentalized by the antagonistic molecular programs of selection, proliferation, and somatic hypermutation respectively. In the bone marrow, an epigenetic reader, BRWD1, orchestrates the sequential stages of B cell progenitor proliferation and B cell receptor recombination. Here, we analyze mice with a conditional knockout of Brwd1 in follicular B cells (Cd23^Cre/wt;Brwd1^fl/fl) and GC B cells (Aicda^Cre/wt;Brwd1^fl/fl) to investigate the functions of BRWD1 during peripheral B cell activation. Compared to Brwd1^fl/fl mice, Cd23^Cre/wt;Brwd1^fl/fl mice show diminished GC B cell responses and class switch recombination after immunization. By contrast, Aicda^Cre/wt;Brwd1^fl/fl mice exhibit increased GC B cell proliferation but defects in affinity maturation and tolerance. Somatic hypermutation and differentiation into memory and plasma cells are intact. RNA-seq and ATAC-seq analyses of GC B cells from Aicda^Cre/wt;Brwd1^fl/fl mice indicate that BRWD1 deficiency alters the transcriptional and epigenetic identities of the LZ, DZp, and DZd states. Our results thus demonstrate that BRWD1 regulates multiple transitions along B cell developmental and activation pathways, suggesting stringent epigenetic control of GC states drives positive and negative selection.