期刊
IMMUNITY
卷 53, 期 1, 页码 143-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2020.06.011
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资金
- Albert G. and Olive H. Schlink Foundation
- Salk Institute T32 Cancer Training Grant [T32CA009370]
- NIGMS NRSA [F32 GM128377-01]
- National Institutes of Health [GM128943, AI151123, CA228211, CA184043, AI107027, OD023689]
- Pew-Stewart Scholar Award for Cancer Research
- V Foundation for Cancer Research [V2016-006]
- Leona M. and Harry B. Helmsley Charitable Trust
- NOMIS Foundation
- Crohn's and Colitis Foundation
- National Cancer Institute [CA014195]
Regulatory T (Treg) cells play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg cell development and function are dependent on the transcription factor Foxp3. Here, we performed a genome-wide CRISPR loss-of-function screen to identify Foxp3 regulators in mouse primary Treg cells. Foxp3 regulators were enriched in genes encoding subunits of the SWI/SNF nucleosome-remodeling and SAGA chromatin-modifying complexes. Among the three SWI/SNF-related complexes, the Brd9-containing non-canonical (nc) BAF complex promoted Foxp3 expression, whereas the PBAF complex was repressive. Chemical-induced degradation of Brd9 led to reduced Foxp3 expression and reduced Treg cell function in vitro. Brd9 ablation compromised Treg cell function in inflammatory disease and tumor immunity in vivo. Furthermore, Brd9 promoted Foxp3 binding and expression of a subset of Foxp3 target genes. Our findings provide an unbiased analysis of the genetic networks regulating Foxp3 and reveal ncBAF as a target for therapeutic manipulation of Treg cell function.
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