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CRISPR screen in regulatory T cells reveals modulators of Foxp3

Author

Listed:
  • Jessica T. Cortez

    (University of California
    University of California
    University of California
    University of California)

  • Elena Montauti

    (Northwestern University Feinberg School of Medicine)

  • Eric Shifrut

    (University of California
    University of California
    University of California)

  • Jovylyn Gatchalian

    (Salk Institute for Biological Studies)

  • Yusi Zhang

    (Northwestern University Feinberg School of Medicine)

  • Oren Shaked

    (University of California
    University of California
    University of California)

  • Yuanming Xu

    (Northwestern University Feinberg School of Medicine)

  • Theodore L. Roth

    (University of California
    University of California
    University of California
    University of California)

  • Dimitre R. Simeonov

    (University of California
    University of California
    University of California
    University of California)

  • Yana Zhang

    (Northwestern University Feinberg School of Medicine)

  • Siqi Chen

    (Northwestern University Feinberg School of Medicine)

  • Zhongmei Li

    (University of California
    University of California
    University of California)

  • Jonathan M. Woo

    (University of California
    University of California
    University of California)

  • Josephine Ho

    (Salk Institute for Biological Studies)

  • Ian A. Vogel

    (University of California
    University of California
    University of California)

  • Grace Y. Prator

    (University of California
    University of California
    University of California)

  • Bin Zhang

    (Northwestern University Feinberg School of Medicine)

  • Youjin Lee

    (University of California
    University of California
    University of California)

  • Zhaolin Sun

    (Dalian Medical University School of Pharmacy)

  • Igal Ifergan

    (Northwestern University Feinberg School of Medicine)

  • Frédéric Van Gool

    (University of California
    University of California)

  • Diana C. Hargreaves

    (Salk Institute for Biological Studies)

  • Jeffrey A. Bluestone

    (University of California
    University of California
    Parker Institute for Cancer Immunotherapy)

  • Alexander Marson

    (University of California
    University of California
    University of California
    Parker Institute for Cancer Immunotherapy)

  • Deyu Fang

    (Northwestern University Feinberg School of Medicine)

Abstract

Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties2, can promote autoimmunity and/or facilitate more effective tumour immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg 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 Treg 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. Treg-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 Treg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Treg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

Suggested Citation

  • Jessica T. Cortez & Elena Montauti & Eric Shifrut & Jovylyn Gatchalian & Yusi Zhang & Oren Shaked & Yuanming Xu & Theodore L. Roth & Dimitre R. Simeonov & Yana Zhang & Siqi Chen & Zhongmei Li & Jonath, 2020. "CRISPR screen in regulatory T cells reveals modulators of Foxp3," Nature, Nature, vol. 582(7812), pages 416-420, June.
  • Handle: RePEc:nat:nature:v:582:y:2020:i:7812:d:10.1038_s41586-020-2246-4
    DOI: 10.1038/s41586-020-2246-4
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    Cited by:

    1. Congyi Lu & Görkem Garipler & Chao Dai & Timothy Roush & Jose Salome-Correa & Alex Martin & Noa Liscovitch-Brauer & Esteban O. Mazzoni & Neville E. Sanjana, 2023. "Essential transcription factors for induced neuron differentiation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Qinchang Chen & Guohui Chuai & Haihang Zhang & Jin Tang & Liwen Duan & Huan Guan & Wenhui Li & Wannian Li & Jiaying Wen & Erwei Zuo & Qing Zhang & Qi Liu, 2023. "Genome-wide CRISPR off-target prediction and optimization using RNA-DNA interaction fingerprints," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Sandor Spisak & David Chen & Pornlada Likasitwatanakul & Paul Doan & Zhixin Li & Pratyusha Bala & Laura Vizkeleti & Viktoria Tisza & Pushpamali Silva & Marios Giannakis & Brian Wolpin & Jun Qi & Nilay, 2024. "Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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