Defining the role of the BCL7 subunit of mammalian SWI/SNF chromatin remodeling complexes in human cancer

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PROJECT SUMMARY/ABSTRACT The mammalian SWI/SNF (mSWI/SNF) complexes represent a family of ATP-dependent chromatin remodeling complexes (CRCs) that play critical roles in the maintenance of chromatin accessibility and gene expression. Mammalian SWI/SNF complexes are combinatorically assembled from 29 different gene products to generate three distinct 11-15-subunit classes termed BAF, pBAF, and ncBAF complexes. Importantly, mSWI/SNF genes are mutated in over 20% of human cancers, underscoring their critical roles in oncogenesis. While biochemical, structural and genomics-based studies over the past several years have begun to define subunit-specific contributions to overall protein complex function, most subunit functions remain unassigned. BCL7 is a recently- discovered component of all three SWI/SNF complex classes. Despite other mSWI/SNF complex subunits being conserved throughout evolution, BCL7 has only recently emerged in higher-order organisms, suggesting it may be necessary for specialized organismal processes such as mammalian cell differentiation or immune system development. I aim to define the role of the BCL7 subunit in mSWI/SNF complex function in the human cell context. I hypothesize that BCL7 is required for a) SWI/SNF complex biochemical integrity; and b) for genome-wide SWI/SNF targeting and DNA accessibility generation in lymphoma and primary B cells. The role of the mammalian-specific BCL7 subunit in the biochemical composition, targeting, and activity of SWI/SNF complexes remains unknown. First, I aim to determine the impact of BCL7 deletion on SWI/SNF complex biochemical integrity (subunit assembly and stability) and to define the region of BCL7 required for its incorporation into SWI/SNF complexes. BCL7 mutations, including deletions and single-residue substitutions, have been identified primarily in lymphomas and myelomas, cancer subtypes that affect B cell maturation and function. Second, I aim to determine the impact of BCL7 perturbations on the SWI/SNF complex genomic targeting, DNA accessibility generation, and subsequent gene expression in B cell lymphomas such as DLBCL. Third, I aim to determine the functional impact and role of BCL7 in SWI/SNF complex genomic targeting and accessibility generation in healthy human primary B cells. This research will elucidate key features of BCL7-mediated SWI/SNF complex composition, chromatin localization, and resulting DNA accessibility, and gene expression programs in normal and malignant B cells. The mechanisms governing chromatin remodeling complex activities during basic cellular processes and in human disease remain incompletely understood, and with the highly frequent mutations in these processes observed in human cancers, this is a uniquely pertinent and high-impact priority for the field at-large.