BCL7A's Arginine Anchor Links Nucleosome Recognition to Chromatin Remodeling and DLBCL Tumor Suppression

Dysfunction of human chromatin remodeling complex SWI/SNF associates with multiple diseases including cancer. BCL7A, a tissue-specific, non-catalytic subunit of this complex, exhibits tumor suppressive activity, especially in diffuse large B-cell lymphoma (DLBCL). However, the underlying mechanism remains elusive. In this study, we use protein structural prediction to identify a conserved arginine anchor in the N-terminal α-helix of BCL7A and demonstrate that this arginine anchor is crucial for the chromatin remodeling activity of the hSWI/SNF complexes. Truncation or DLBCL-associated mutations of this anchor impair BCL7A's tumor-suppressive function without affecting its integration into the complexes. Instead, these mutations lead to decreased BCL7A occupancy at target loci and reduced chromatin accessibility and transcriptional regulation. In vivo and cellular assays further validate the pivotal role of the arginine anchor in BCL7A-mediated tumor suppression. Mechanistically, we reveal that BCL7A regulates histone displacement, and its arginine anchor and the SMARCB1 subunit work cooperatively to regulate the remodeling activity of cBAF complexes. Altogether, our study identifies the BCL7A arginine anchor as a key molecular switch that links nucleosome binding to chromatin remodeling and tumor suppression, making it a potential therapeutic target for DLBCL.