Leveraging the BAF chromatin remodeling complex for targeted transcriptional rewiring in cancer

Abstract Chromatin accessibility is essential for maintaining the fidelity of gene regulation and is dynamically regulated by epigenetic enzymes that are often dysregulated in cancer. The most commonly mutated regulator is the modular, multi-subunit Brahma-associated factor (BAF) chromatin remodeling complex. Previous attempts to exploit BAF complex mutations as potential tumor vulnerabilities using loss-of-function approaches have shown limited clinical success. Here, we instead propose a gain-of-function (GOF) strategy and establish Transcriptional/Remodeling chemical Inducers of Proximity (TRIPs), a class of neomorphic molecules that recruit active BAF complexes to rewire an oncogenic repressor, B-cell lymphoma 6 (BCL6). TRIPs potently induce transcriptional de-repression and apoptosis in Diffuse Large B-cell Lymphoma (DLBCL), enabled by ternary complex formation between BCL6 and BAF. CRISPR knockout screening identifies the PBAF complex as an essential contributor to cellular TRIP efficacy. Finally, we demonstrate that TRIP induces chromatin enrichment of BAF at BCL6-bound sites, resulting in ATPase-dependent eviction of BCL6, and de-repression of pro-apoptotic BCL6 target genes. We establish BAF recruitment for targeted chromatin remodeling as a viable GOF pharmacological strategy for tackling diseases driven by aberrant gene repression.