Brg1-dependent enhancer-promoter interactions support B cell activation and germinal center formation
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ABSTRACT:
PROVIDER: PRJNA750329 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description:The Germinal center is a dynamic microenvironment wherein B cells expressing high affinity antibody variants produced by hypermutation are selected for clonal expansion by limiting numbers of T follicular helper cells. Although a great deal is known about the mechanisms that control B cell selection in the germinal center, far less is understood about the clonal behavior of the T follicular helper cells that regulate this process. Here we report on the dynamic behavior of clones of T follicular helper cells during the germinal center reaction. We find that like germinal center B cells, T follicular helper cells undergo antigen dependent selection during the germinal center reaction resulting in differential proliferative expansion and contraction. Increasing the amount of antigen presented in the germinal center leads to increased T follicular cell division. Competition between T follicular helper cell clones is mediated by T cell receptor affinity for peptide-MHC ligand. Higher affinity T cells expanding preferentially in the germinal center show increased expression of genes downstream of the T cell receptor, genes required for metabolic reprogramming, cell division and cytokine production. These dynamic changes lead to dramatic remodeling of the functional T follicular cell repertoire during the germinal center reaction.
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