Brg1-dependent enhancer-promoter interactions support B cell activation and germinal center formation

Activation and differentiation of B cells depend on extensive rewiring of gene expression networks through changes in chromatin structure and accessibility. The chromatin remodeling complex BAF with its catalytic subunit Brg1 was previously identified as an essential regulator of early B cell development, however, how Brg1 orchestrates gene expression during mature B cell activation is less clear. Here, we find that Brg1 is required for B cell proliferation and germinal center formation through selective interactions with enhancers. Brg1 recruitment to enhancers was associated with increased chromatin accessibility and transcriptional activation of their coupled promoters following B cell activation and expression of cell cycle-associated genes. Accordingly, Brg1-deficient B cells were unable to mount germinal center reactions and support the formation of class-switch plasma cells. Our findings show that changes in B cell transcriptomes that support cell proliferation and GC formation depend on enhancer activation by Brg1. Thus, the BAF complex plays a critical role during the onset of the humoral immune response. Overall design: RNA-seq and ATAC-seq of activated B cells, harvested after 96 hours activation using LPS and IL-4.

B细胞的活化与分化，依赖于通过染色质结构及可及性改变实现的基因表达网络大规模重编程。此前研究已鉴定出，以Brg1为催化亚基的BAF染色质重塑复合物是早期B细胞发育的关键调控因子，但Brg1在成熟B细胞活化过程中如何协调基因表达，目前仍不甚明确。本研究发现，Brg1通过与增强子的选择性互作，是B细胞增殖与生发中心（germinal center，GC）形成所必需的。在B细胞活化及细胞周期相关基因表达后，Brg1被招募至增强子处，这与染色质可及性升高以及其偶联启动子的转录激活密切相关。相应地，Brg1缺陷型B细胞无法引发生发中心反应，也无法支持类别转换浆细胞的形成。本研究结果表明，支持B细胞增殖与GC形成的转录组变化，依赖于Brg1介导的增强子激活。由此可见，BAF复合物在体液免疫应答启动阶段发挥关键调控作用。实验设计：采用脂多糖（Lipopolysaccharide，LPS）与白细胞介素-4（Interleukin-4，IL-4）活化B细胞，于活化96小时后收集细胞，对其进行RNA测序（RNA-seq）与转座酶可及性测序（ATAC-seq）。