A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function
A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function
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DOI：
10.1016/j.immuni.2020.06.011
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发表时间：
2020-07-14
期刊：
影响因子：
32.4
通讯作者：
Zheng, Ye
中科院分区：
文献类型：
--
作者：
Loo, Chin-San;Gatchalian, Jovylyn;Zheng, Ye
调节性T细胞（Treg）在抑制自身反应性T细胞和维持免疫稳态中起关键作用。Treg细胞的发育和功能依赖于转录因子Foxp3。在这里，我们进行了全基因组CRISPR功能缺失筛选，以鉴定小鼠原代Treg细胞中的Foxp3调节因子。Foxp3调节因子富含编码SWI/SNF核小体重塑和SAGA染色质修饰复合物亚基的基因。在三个SWI/ snf相关复合物中，含有brd9的非规范（nc） BAF复合物促进Foxp3的表达，而PBAF复合物抑制Foxp3的表达。化学诱导的Brd9降解导致Foxp3表达降低，Treg细胞功能降低。Brd9消融术损害Treg细胞在体内炎症疾病和肿瘤免疫中的功能。此外，Brd9促进Foxp3结合和Foxp3靶基因亚群的表达。我们的研究结果对调节Foxp3的遗传网络进行了公正的分析，并揭示了ncBAF作为Treg细胞功能治疗操作的靶标。
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.