Abstract IA014: SWI/SNF complexes in development and disease


 The Hargreaves laboratory is focused on understanding the molecular mechanisms of SWI/SNF complex function in immune cell differentiation and response relating to cancer and inflammation. SWI/SNF complexes are broadly required for embryonic development and cellular differentiation. Mutations in SWI/SNF complex genes are observed in ~20% of human cancers and in a number of rare intellectual disability disorders. However, it remains unclear how SWI/SNF complexes mechanistically regulate cellular differentiation through complex targeting, engagement with transcription factors, and function in transcription. We approach these questions in immune cells by employing molecular and proteomic methods in conjunction with next-generation sequencing approaches with the ultimate goal of connecting the functions of specific SWI/SNF subunits to the regulation of specific gene networks important for inflammatory responses and immune cell differentiation. This approach has allowed us to reveal the role of the canonical BAF complex (cBAF) in the establishment and maintenance of epigenetic transitions that occur during cellular differentiation, including activation of cell type-specific enhancers and engagement of transcription factors. Further, we and others have identified a new variant, referred to as the noncanonical BAF (ncBAF) complex, which exhibits distinct modes of targeting, unique regulatory interactions, and specific function in inflammatory gene transcription (Ahmed, Gatchalian et al PNAS 2022). Following up on the identification of the ncBAF subunit Brd9 in a CRISPR genome wide screen for regulators of Foxp3 performed in collaboration with the Zheng lab at the Salk Institute, we performed sgRNA knockdown to identify the role of each of the three SWI/SNF complex variants (BAF, ncBAF, and PBAF) (Loo, Gatchalian et al Immunity 2020). We found that ncBAF positively regulates the expression of Foxp3, while PBAF complexes negatively regulate Foxp3. Using epigenomic and transcriptomic analysis in Tregs following knockdown or chemical degradation of BRD9, we found that BRD9 positively regulates Foxp3 expression and its target genes by stabilizing Foxp3 binding at BRD9/Foxp3 co-bound sites, including at the Foxp3 locus. In an MC38 colorectal cancer model, transfer of Brd9 deficient Tregs resulted in significantly slower tumor growth than control Tregs, with increased infiltration of IFN-γ producing CD8 and CD4 T cells, suggesting that Brd9 deletion in Tregs reduces Treg-mediated suppression of anti-tumor responses. Thus, these results highlight BRD9 and the ncBAF complex as novel targets that could be exploited to manipulate Treg function in cancer.
 Citation Format: Jovylyn Gatchalian, Nasiha Ahmed, Chin-San Loo, Ye Zheng, Diana C. Hargreaves. SWI/SNF complexes in development and disease. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA014.