Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient GC B cell responses [ATAC-seq]
Differentiating B cells in germinal centers (GC) require tightly coordinated transcriptional and epigenetic transitions to generate efficient humoral immune responses. The mammalian BAF (Brg1/Brm-associated factor) complexes are major regulators of nucleosomal remodeling, crucial for cellular differentiation and development, and are commonly mutated in several cancers, including GC-derived B cell lymphomas. However, the specific roles of distinct BAF complexes in GC B cell biology and the generation of functional humoral immune responses are not well-understood. Here, we show that the Arid1a-dependent canonical BAF (cBAF) complex is indispensable for generatingon of fully mature GCs and high affinity humoral immune responses. While Arid1a-deficient B cells undergo activation to initiate GC responses, they fail to sustain the GC program, resulting incausing premature GC collapse. Mechanistically, Arid1a-dependent cBAF activity establishes permissive chromatin landscapes at several thousand genomic regions during B cell activation and isare concomitantly required to suppress inflammatory gene programs to maintain transcriptional fidelity in early GC B cells. Interestingly, the inflammatory signatures instigated by Arid1a- deficiency in early GC B cells recruits neutrophils and inflammatory monocytes, and eventually disrupts GC homeostasis. Remarkably, dampening of inflammatory cues with anti-inflammatory glucocorticoid receptor signaling rescues GC B cell differentiation of Arid1a-deficient B cells, thus highlighting a critical role of inflammation in impeding GC responses. In sum, our work identifies essential functions of Arid1a-dependent BAF activity in promoting efficient GC responses. These findings further support recent paradigms uncovering a deterministic role of unrestrained inflammation in obstructing GC responses, common in patients with severe bacterial and viral infections. Overall design: To investigate the changes of chromatin accesibility in Arid1a KO in B cells, using Cd19 or Cg1cre