BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function

Abstract

ABSTRACTGerminal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation andIgkrecombination. We hypothesized BRWD1 might play similar insulative roles in the periphery. InBrwd1-/-follicular B cells, GC initiation and class switch recombination following immunization were inhibited. In contrast, inBrwd1-/-GC B cells there was admixing of chromatin accessibility across GC subsets and transcriptional dysregulation including induction of inflammatory pathways. This global molecular GC dysregulation was associated with specific defects in proliferation, affinity maturation, and tolerance. These data suggest that GC subset identity is required for some but not all GC-attributed functions. Furthermore, these data demonstrate a central role for BRWD1 in orchestrating epigenetic transitions at multiple steps along B cell developmental and activation pathways.