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Epigenome editing technologies for discovery and medicine

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Abstract

Epigenome editing has rapidly evolved in recent years, with diverse applications that include elucidating gene regulation mechanisms, annotating coding and noncoding genome functions and programming cell state and lineage specification. Importantly, given the ubiquitous role of epigenetics in complex phenotypes, epigenome editing has unique potential to impact a broad spectrum of diseases. By leveraging powerful DNA-targeting technologies, such as CRISPR, epigenome editing exploits the heritable and reversible mechanisms of epigenetics to alter gene expression without introducing DNA breaks, inducing DNA damage or relying on DNA repair pathways.

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Fig. 1: Schematic of CRISPR-based nucleases, base editors, prime editors and epigenome editors with a detailed panel of various epigenome-editing platforms.
Fig. 2: Schematic depicting the epigenetic regulation of gene expression.
Fig. 3: Schematic displaying gRNA library design for screens of genes and noncoding elements with various screening readouts.
Fig. 4: Schematic of ex vivo and in vivo applications of epigenome engineering.

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Acknowledgements

We thank Gersbach laboratory members and collaborators for feedback and helpful discussions. This work was supported by National Institutes of Health grants U01AI146356, UM1HG012053, R01MH125236, R01CA289574 and RM1HG011123, National Science Foundation grant EFMA-1830957, DARPA grant HR0011-19-2-0008, the Foundation for Prader–Willi Research, an Allen Distinguished Investigator Award from the Paul G. Allen Frontiers Group to C.A.G., the Open Philanthropy Project and the Duke–Coulter Translational Partnership.

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  1. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Sean R. McCutcheon, Dahlia Rohm, Nahid Iglesias & Charles A. Gersbach

  2. Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA

    Sean R. McCutcheon, Dahlia Rohm, Nahid Iglesias & Charles A. Gersbach

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S.R.M., D.R., N.I. and C.A.G. are named inventors on patent applications related to epigenome-engineering technologies. C.A.G. is a cofounder of Tune Therapeutics and Locus Biosciences and is an advisor to Sarepta Therapeutics.

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McCutcheon, S.R., Rohm, D., Iglesias, N. et al. Epigenome editing technologies for discovery and medicine. Nat Biotechnol 42, 1199–1217 (2024). https://doi.org/10.1038/s41587-024-02320-1

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