CRISPR screen in regulatory T cells reveals modulators of Foxp3

doi:10.1038/s41586-020-2246-4

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2246-4
	CRISPR screen in regulatory T cells reveals modulators of Foxp3
	Xu, Daqian 1,2,3; Wang, Zheng 4; Xia, Yan 5,6; Shao, Fei 7,8; Xia, Weiya 3; Wei, Yongkun 3; Li, Xinjian 9; Qian, Xu 10; Lee, Jong-Ho 11; Du, Linyong 12; Zheng, Yanhua 5; Lv, Guishuai 13; Leu, Jia-shiun 14; Wang, Hongyang 13; Xing, Dongming 15; Liang, Tingbo 1,2; Hung, Mien-Chie 16,17,18; Lu, Zhimin 7,8,19
	2020-04-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
文章类型	Article;Early Access
语种	英语
国家	USA; Peoples R China
英文关键词	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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000529600400007
WOS关键词	TRANSCRIPTION FACTOR FOXP3 ; SUPPRESSIVE FUNCTION ; CIS-ELEMENT ; ACTIVATION ; GENE ; GENERATION ; EXPRESSION ; ENHANCERS ; IDENTITY ; INSTABILITY
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281336
专题	地球科学资源环境科学气候变化
作者单位	1.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Inst Translat Med,Dept Hepatobiliary & Pancreat S, Hangzhou, Peoples R China; 2.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Zhejiang Prov Key Lab Pancreat Dis, Hangzhou, Peoples R China; 3.Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA; 4.Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA; 5.Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA; 6.Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA; 7.Qingdao Univ, Affiliated Hosp, Qingdao, Peoples R China; 8.Qingdao Canc Inst, Qingdao, Peoples R China; 9.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, CAS Key Lab Infect & Immun, Beijing, Peoples R China; 10.Nanjing Med Univ, Sch Publ Hlth, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Peoples R China; 11.Dong A Univ, Dept Biol Sci, Busan, South Korea; 12.Wenzhou Med Univ, Sch Lab Med & Life Sci, Minist Educ China, Key Lab Lab Med, Wenzhou, Peoples R China; 13.Second Mil Med Univ, Eastern Hepatobiliary Surg Inst, Int Cooperat Lab Signal Transduct, Shanghai, Peoples R China; 14.Houston Methodist Res Inst, Dept Neurosurg, Houston, TX USA; 15.Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China; 16.China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan; 17.China Med Univ, Ctr Mol Med, Taichung, Taiwan; 18.China Med Univ, Off President, Taichung, Taiwan; 19.Zhejiang Univ, Affiliated Hosp 1, Inst Translat Med, Sch Med,Zhejiang Prov Key Lab Pancreat Dis, Hangzhou, Peoples R China
推荐引用方式 GB/T 7714	Xu, Daqian,Wang, Zheng,Xia, Yan,et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3[J]. NATURE,2020.
APA	Xu, Daqian.,Wang, Zheng.,Xia, Yan.,Shao, Fei.,Xia, Weiya.,...&Lu, Zhimin.(2020).CRISPR screen in regulatory T cells reveals modulators of Foxp3.NATURE.
MLA	Xu, Daqian,et al."CRISPR screen in regulatory T cells reveals modulators of Foxp3".NATURE (2020).