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Crosstalk between CRISPR-Cas9 and the human transcriptome

Author

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  • Aaron A. Smargon

    (University of California San Diego
    University of California San Diego, Sanford Consortium for Regenerative Medicine
    University of California San Diego)

  • Assael A. Madrigal

    (University of California San Diego
    University of California San Diego, Sanford Consortium for Regenerative Medicine
    University of California San Diego)

  • Brian A. Yee

    (University of California San Diego
    University of California San Diego, Sanford Consortium for Regenerative Medicine
    University of California San Diego)

  • Kevin D. Dong

    (University of California San Diego
    University of California San Diego, Sanford Consortium for Regenerative Medicine
    University of California San Diego)

  • Jasmine R. Mueller

    (University of California San Diego
    University of California San Diego, Sanford Consortium for Regenerative Medicine
    University of California San Diego)

  • Gene W. Yeo

    (University of California San Diego
    University of California San Diego, Sanford Consortium for Regenerative Medicine
    University of California San Diego)

Abstract

CRISPR-Cas9 expression independent of its cognate synthetic guide RNA (gRNA) causes widespread genomic DNA damage in human cells. To investigate whether Cas9 can interact with endogenous human RNA transcripts independent of its guide, we perform eCLIP (enhanced CLIP) of Cas9 in human cells and find that Cas9 reproducibly interacts with hundreds of endogenous human RNA transcripts. This association can be partially explained by a model built on gRNA secondary structure and sequence. Critically, transcriptome-wide Cas9 binding sites do not appear to correlate with published genome-wide Cas9 DNA binding or cut-site loci under gRNA co-expression. However, even under gRNA co-expression low-affinity Cas9-human RNA interactions (which we term CRISPR crosstalk) do correlate with published elevated transcriptome-wide RNA editing. Our findings do not support the hypothesis that human RNAs can broadly guide Cas9 to bind and cleave human genomic DNA, but they illustrate a cellular and RNA impact likely inherent to CRISPR-Cas systems.

Suggested Citation

  • Aaron A. Smargon & Assael A. Madrigal & Brian A. Yee & Kevin D. Dong & Jasmine R. Mueller & Gene W. Yeo, 2022. "Crosstalk between CRISPR-Cas9 and the human transcriptome," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28719-5
    DOI: 10.1038/s41467-022-28719-5
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    References listed on IDEAS

    as
    1. Mazhar Adli, 2018. "The CRISPR tool kit for genome editing and beyond," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. Julian Grünewald & Ronghao Zhou & Sara P. Garcia & Sowmya Iyer & Caleb A. Lareau & Martin J. Aryee & J. Keith Joung, 2019. "Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors," Nature, Nature, vol. 569(7756), pages 433-437, May.
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