Understanding the Role of SWI/SNF complex in Development and Disease

The SWI/SNF chromatin remodeling complex plays a critical role in modulating DNA accessibility and consequently regulating downstream gene expression during development and disease. This dissertation focuses on comprehensively defining the functions of Bicra/GLTSCR1 in hematopoiesis and the role of SMARCC2 in neuroendocrine differentiation of prostate cancer. Our lab identified a novel GLTSCR1 containing BAF subcomplex; GBAF. To determine the unknown function of Bicra/GLTSCR1, we generated a CRISPR knockout mouse model for Bicra. Through a series of histological assays, flow cytometry assays, and genomic profiling we establish that Bicra/GLTSCR1 plays a critical role in red blood cell enucleation via central macrophages in fetal liver. In the latter half of the dissertation, I focus on prostate cancer. The treatment-emergent neuroendocrine prostate cancer (TE-NEPC) subtype is a highly aggressive disease state with limited curative strategies. While a few subunits of the SWI/SNF complex are known to be upregulated in TE-NEPC, the underlying biological mechanism remains unclear. The findings of this research establish a dynamic switch in the core structural SWI/SNF subunits upon neuroendocrine differentiation (NED). Furthermore, a phenotypic assay and RNA-seq analysis pinpoint the reduced neuroendocrine differentiation potential upon knockdown of SMARCC2. I also identify a novel alternatively spliced SMARCC2 isoform that is exclusively expressed upon NED and favors the formation of the Polybromo1 containing Brg1 associated factor (PBAF) subcomplex. Overall, I define a unique role for SWI/SNF complex subunits in cell fate and lineage commitment during normal hematopoiesis and malignant prostate cancer progression. Further elucidating the context-dependent function of the SWI/SNF complex may reveal new therapeutic opportunities in hematologic and prostate malignancies.