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In vivo base editing of post-mitotic sensory cells

Author

Listed:
  • Wei-Hsi Yeh

    (Harvard University
    Harvard University
    Broad Institute of MIT and Harvard
    Massachusetts Eye and Ear)

  • Hao Chiang

    (Massachusetts Eye and Ear
    Harvard Medical School)

  • Holly A. Rees

    (Harvard University
    Harvard University
    Broad Institute of MIT and Harvard)

  • Albert S. B. Edge

    (Massachusetts Eye and Ear
    Harvard Medical School
    Harvard Medical School
    Harvard Stem Cell Institute)

  • David R. Liu

    (Harvard University
    Harvard University
    Broad Institute of MIT and Harvard)

Abstract

Programmable nucleases can introduce precise changes to genomic DNA through homology-directed repair (HDR). Unfortunately, HDR is largely restricted to mitotic cells, and is typically accompanied by an excess of stochastic insertions and deletions (indels). Here we present an in vivo base editing strategy that addresses these limitations. We use nuclease-free base editing to install a S33F mutation in β-catenin that blocks β-catenin phosphorylation, impedes β-catenin degradation, and upregulates Wnt signaling. In vitro, base editing installs the S33F mutation with a 200-fold higher editing:indel ratio than HDR. In post-mitotic cells in mouse inner ear, injection of base editor protein:RNA:lipid installs this mutation, resulting in Wnt activation that induces mitosis of cochlear supporting cells and cellular reprogramming. In contrast, injection of HDR agents does not induce Wnt upregulation. These results establish a strategy for modifying posttranslational states in signaling pathways, and an approach to precision editing in post-mitotic tissues.

Suggested Citation

  • Wei-Hsi Yeh & Hao Chiang & Holly A. Rees & Albert S. B. Edge & David R. Liu, 2018. "In vivo base editing of post-mitotic sensory cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04580-3
    DOI: 10.1038/s41467-018-04580-3
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    Cited by:

    1. Ogahara, Zoë & Jespersen, Kristjan & Theilade, Ida & Nielsen, Martin Reinhard, 2022. "Review of smallholder palm oil sustainability reveals limited positive impacts and identifies key implementation and knowledge gaps," Land Use Policy, Elsevier, vol. 120(C).
    2. Katarina Kulhankova & Soumba Traore & Xue Cheng & Hadrien Benk-Fortin & Stéphanie Hallée & Mario Harvey & Joannie Roberge & Frédéric Couture & Sajeev Kohli & Thomas J. Gross & David K. Meyerholz & Gar, 2023. "Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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