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Mitochondrial base editor induces substantial nuclear off-target mutations

Author

Listed:
  • Zhixin Lei

    (Peking University
    Peking University)

  • Haowei Meng

    (Peking University)

  • Lulu Liu

    (Peking University)

  • Huanan Zhao

    (Tsinghua University
    Peking University–Tsinghua University–National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University)

  • Xichen Rao

    (Peking University)

  • Yongchang Yan

    (Peking University
    Peking University)

  • Hao Wu

    (Peking University
    Peking University)

  • Min Liu

    (Peking University
    Peking University)

  • Aibin He

    (Peking University
    Peking University)

  • Chengqi Yi

    (Peking University
    Peking University
    Peking University
    Peking University Genome Editing Research Center, Peking University)

Abstract

DddA-derived cytosine base editors (DdCBEs)—which are fusions of split DddA halves and transcription activator-like effector (TALE) array proteins from bacteria—enable targeted C•G-to-T•A conversions in mitochondrial DNA1. However, their genome-wide specificity is poorly understood. Here we show that the mitochondrial base editor induces extensive off-target editing in the nuclear genome. Genome-wide, unbiased analysis of its editome reveals hundreds of off-target sites that are TALE array sequence (TAS)-dependent or TAS-independent. TAS-dependent off-target sites in the nuclear DNA are often specified by only one of the two TALE repeats, challenging the principle that DdCBEs are guided by paired TALE proteins positioned in close proximity. TAS-independent off-target sites on nuclear DNA are frequently shared among DdCBEs with distinct TALE arrays. Notably, they co-localize strongly with binding sites for the transcription factor CTCF and are enriched in topologically associating domain boundaries. We engineered DdCBE to alleviate such off-target effects. Collectively, our results have implications for the use of DdCBEs in basic research and therapeutic applications, and suggest the need to thoroughly define and evaluate the off-target effects of base-editing tools.

Suggested Citation

  • Zhixin Lei & Haowei Meng & Lulu Liu & Huanan Zhao & Xichen Rao & Yongchang Yan & Hao Wu & Min Liu & Aibin He & Chengqi Yi, 2022. "Mitochondrial base editor induces substantial nuclear off-target mutations," Nature, Nature, vol. 606(7915), pages 804-811, June.
    • Handle: RePEc:nat:nature:v:606:y:2022:i:7915:d:10.1038_s41586-022-04836-5
    DOI: 10.1038/s41586-022-04836-5
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    Cited by:

    1. Friedrich Fauser & Bhakti N. Kadam & Sebastian Arangundy-Franklin & Jessica E. Davis & Vishvesha Vaidya & Nicola J. Schmidt & Garrett Lew & Danny F. Xia & Rakshaa Mureli & Colman Ng & Yuanyue Zhou & N, 2024. "Compact zinc finger architecture utilizing toxin-derived cytidine deaminases for highly efficient base editing in human cells," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Haifeng Sun & Zhaojun Wang & Limini Shen & Yeling Feng & Lu Han & Xuezhen Qian & Runde Meng & Kangming Ji & Dong Liang & Fei Zhou & Xin Lou & Jun Zhang & Bin Shen, 2023. "Developing mitochondrial base editors with diverse context compatibility and high fidelity via saturated spacer library," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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