Genome-wide CRISPR screens revealed a reciprocal role of SWI/SNF complexes in controlling regulatory T cell function

Abstract

Abstract Regulatory T cells (Tregs) are a specialized immune population that act to suppress overactive inflammatory response and maintain immune homeostasis. There is of great interest in harnessing Treg for controlling autoimmune disease or boosting anti-tumor immunity. Since the transcription factor, Forkhead box P3 (Foxp3), is known to control Treg development and function, understanding the regulation of Foxp3 could potentially lead to the development of therapeutics for treating autoimmune diseases and cancer. Here we performed a genome-wide CRISPR/Cas9 knockout screen to identify the regulators of Foxp3 in mouse primary Tregs. The results showed that Foxp3 regulators are highly enriched in genes encoding chromatin regulators, such as SAGA and SWI/SNF complexes. Among the SWI/SNF complexes, the GBAF complex promoted Foxp3 expression, whereas the PBAF complex repressed its expression. Functional genomic studies revealed that both GBAF and PBAF co-localized with Foxp3 in genome-wide binding sites. Targeting of GBAF reduced Foxp3 binding and altered expression a subset of Foxp3 target genes, indicating that GBAF actively participates in the Foxp3-dependent transcriptional program. Importantly, Treg suppressor function can be manipulated by targeting GBAF or PBAF, demonstrating in in vitro suppression assay, as well as mouse in autoimmune diseases and tumor model. Collectively, we provide an unbiased analysis of genes and networks regulating Foxp3, and reveal SWI/SNF complexes, GBAF and PBAF, as novel targets that could be exploited to manipulate Treg function for therapeutics of autoimmune diseases and cancer.