CRISPR screen in regulatory T cells reveals modulators of Foxp3

Cortez Jessica T.; Montauti Elena; Shifrut Eric; Gatchalian Jovylyn; Zhang Yusi; Shaked Oren; Xu Yuanming; Roth Theodore L.; Simeonov Dimitre R.; Zhang Yana; Chen Siqi; Li Zhongmei; Woo Jonathan M.; Ho Josephine; Vogel Ian A.; Prator Grace Y.; Zhang Bin; Lee Youjin; Sun Zhaolin; Ifergan Igal; Van Gool Frederic; Hargreaves Diana C.; Bluestone Jeffrey A.; Marson Alexander; Fang Deyu

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CRISPR screen in regulatory T cells reveals modulators of Foxp3

机译：调节性T细胞中的Cr Crpr筛网显示Foxp3的调节剂

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Regulatory T (T-reg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity(1). Conversely, T-reg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties(2), can promote autoimmunity and/or facilitate more effective tumour immunity(3,4). A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective T-reg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse T-reg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. T-reg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient T-reg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in T-reg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for T-reg immunotherapies for cancer and autoimmune disease.A CRISPR-based screening platform was used to identify previously uncharacterized genes that regulate the regulatory T cell-specific master transcription factor Foxp3, indicating that this screening method may be broadly applicable for the discovery of other genes involved in autoimmunity and immune responses to cancer.

机译：调节性T（T-REG）细胞需要控制免疫应答并维持稳态，但对抗肿瘤免疫力（1）的显着障碍。相反，T-REG不稳定性，其特征在于损失母体转录因子Foxp3和获取促炎特性（2），可以促进自身免疫和/或促进更有效的肿瘤免疫（3,4）。全面了解调节Foxp3的途径可能导致对自身免疫性疾病和癌症的更有效的T-Reg疗法。新的功能遗传工具的可用性使得能够系统疏远调节FoxP3表达的基因调节程序的可能性。在这里，我们开发了一种基于CRISPR的汇集筛查平台，用于初级小鼠T-REG细胞中的表型，并应用该技术进行大约500个核因子的有针对性的函数屏幕，以识别促进或破坏FOXP3表达的基因监管计划。我们鉴定了几种FoxP3表达的调节剂，包括泛素特异性肽酶22（USP22）和无名指蛋白20（RNF20）。 USP22，Saga染色质改性复合物的脱水模块的成员，显示为稳定Foxp3表达的阳性调节剂;虽然筛选表明RNF20，E3泛素连接酶，可以用作Foxp3的负调节剂。在小鼠中的T-Reg特异性消融USP22降低了Foxp3蛋白水平，并导致其抑制功能的缺陷导致自发的自身免疫，但保护了多种癌症模型中的肿瘤生长。通过烧蚀RNF20，可以拯救在USP22缺陷细胞中的FOXP3稳定化，揭示T-REG细胞中的互易泛素开关。这些结果显示了Foxp3的先前未知的调节剂，并证明了可以广泛应用于发现癌症和自身免疫性疾病的新靶标的筛选方法。基于CRISPR的筛查平台用于鉴定调节监管的先前无表征性基因。 T细胞特异性母系转录因子FoxP3，表明该筛查方法可以广泛适用于发现涉及自身免疫和免疫应答的其他基因对癌症。

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来源
《Nature》 |2020年第7812期|416-420|共5页
作者
Cortez Jessica T.; Montauti Elena; Shifrut Eric; Gatchalian Jovylyn; Zhang Yusi; Shaked Oren; Xu Yuanming; Roth Theodore L.; Simeonov Dimitre R.; Zhang Yana; Chen Siqi; Li Zhongmei; Woo Jonathan M.; Ho Josephine; Vogel Ian A.; Prator Grace Y.; Zhang Bin; Lee Youjin; Sun Zhaolin; Ifergan Igal; Van Gool Frederic; Hargreaves Diana C.; Bluestone Jeffrey A.; Marson Alexander; Fang Deyu;
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Univ Calif San Francisco Biomed Sci Grad Program San Francisco CA 94143 USA|Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Northwestern Univ Dept Pathol Feinberg Sch Med Chicago IL 60611 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Salk Inst Biol Studies Mol & Cellular Biol Lab 10010 N Torrey Pines Rd La Jolla CA 92037 USA;

Northwestern Univ Dept Pathol Feinberg Sch Med Chicago IL 60611 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Northwestern Univ Dept Pathol Feinberg Sch Med Chicago IL 60611 USA;

Univ Calif San Francisco Biomed Sci Grad Program San Francisco CA 94143 USA|Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Univ Calif San Francisco Biomed Sci Grad Program San Francisco CA 94143 USA|Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Northwestern Univ Dept Pathol Feinberg Sch Med Chicago IL 60611 USA;

Northwestern Univ Dept Med Div Hematol Oncol Robert H Lurie Comprehens Canc Ctr Feinberg Sch M Chicago IL 60611 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Salk Inst Biol Studies Mol & Cellular Biol Lab 10010 N Torrey Pines Rd La Jolla CA 92037 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Northwestern Univ Dept Med Div Hematol Oncol Robert H Lurie Comprehens Canc Ctr Feinberg Sch M Chicago IL 60611 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA;

Dalian Med Univ Dept Pharmacol Sch Pharm Dalian Peoples R China;

Northwestern Univ Dept Microbiol & Immunol Feinberg Sch Med Chicago IL 60611 USA;

Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif San Francisco Sean N Parker Autoimmune Res Lab San Francisco CA 94143 USA;

Salk Inst Biol Studies Mol & Cellular Biol Lab 10010 N Torrey Pines Rd La Jolla CA 92037 USA;

Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif San Francisco Sean N Parker Autoimmune Res Lab San Francisco CA 94143 USA|Parker Inst Canc Immunotherapy San Francisco CA 94129 USA;

Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA|Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA|Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA|Parker Inst Canc Immunotherapy San Francisco CA 94129 USA|Univ Calif San Francisco UCSF Helen Diller Family Comprehens Canc Ctr San Francisco CA 94143 USA|Univ Calif San Francisco Dept Med San Francisco CA 94143 USA|Chan Zuckerberg Biohub San Francisco CA 94158 USA|Univ Calif San Francisco Rosalind Russell Ephraim P Engleman Rheumatol Res San Francisco CA 94143 USA;

Northwestern Univ Dept Pathol Feinberg Sch Med Chicago IL 60611 USA;

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3. Androgen receptor modulates Foxp3 expression in CD4(+)CD25(+)Foxp3(+) regulatory T-cells [J] . Walecki Magdalena, Eisel Florian, Klug Joerg, Molecular biology of the cell . 2015,第15期

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6. A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function [O] . Chin-San Loo, Jovylyn Gatchalian, Yuqiong Liang, -1

机译：全基因组的CRISPR屏幕揭示了Foxp3表达和调节性T细胞功能中非规范的核小体重塑BAF复合体的作用。
7. CRISPR screen in regulatory T cells reveals modulators of Foxp3 [O] . Jessica T. Cortez, Elena Montauti, Eric Shifrut, 2020

机译：调节性T细胞中的Cr Crpr筛网显示Foxp3的调节剂

CRISPR screen in regulatory T cells reveals modulators of Foxp3

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