Dysregulation of mSWI/SNF (BAF) Complexes in Human Malignancy

Abstract

Mammalian SWI/SNF (mSWI/SNF or BAF) complexes are multi-subunit, ATP-dependent, chromatin-remodeling protein complexes that increase the accessibility of DNA to transcriptional machinery. BAF complex perturbations are found frequently in both cancer and neurodevelopmental disorders. The genes encoding BAF complex subunits are mutated in over 20% of human malignancies and BAF complex activities are further altered by additional mechanisms in cancer, such as through their interactions with oncogenic transcription factors and fusion proteins. However, the specific mechanisms of BAF complex dysregulation and their contribution to oncogenesis remain unknown in most malignancies. Here, we studied BAF complex dysregulation in two distinct cancer contexts: myxoid liposarcoma (MLPS) and lymphoma. MLPS is most frequently driven by the FUS-DDIT3 fusion oncoprotein. We find that FUS-DDIT3 dysregulates BAF complexes by interfering with the genomic binding of CEBPB, a critical transcription factor in early adipogenesis. By preventing genomic binding of CEBPB, FUS-DDIT3 inhibits BAF complex targeting to and activation of adipogenic enhancers. We find that collaboration between CEBPB and BAF complexes is essential for the activation of adipogenic enhancers upon FUS-DDIT3 suppression in MLPS and during physiological adipogenesis of mesenchymal stem cells. We also studied BCL7A, a pan-BAF complex subunit that is frequently mutated or silenced in lymphoid malignancies. We find that deletion of BCL7A leads to decreased BAF complex occupancy over sites associated with NF-kB/REL pathway factor and EBF1 motifs, as well as decreased NF-kB/REL pathway factor and EBF1 occupancy on the genome. These preliminary data suggest that BCL7A may accommodate the binding of BAF complexes and specific transcription factors to genomic sites that are critical for normal lymphocyte biology and that BCL7A loss due to mutation or silencing may contribute to specific aspects of lymphomagenesis. Together, the work in this dissertation demonstrates that BAF complexes may be perturbed by multiple, distinct mechanisms in cancer. Studying BAF complex perturbations in diverse malignant contexts is not only essential for increasing our understanding of cancer biology, but also for advancing the clinical care of patients. Investigating the specific mechanisms by which BAF complex dysregulation contributes to human malignancy will facilitate the identification of novel strategies for more targeted and effective cancer therapeutics.