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The role of KRAB zinc-finger proteins in expanding the domestication potential of transposable elements

Nature Genetics (2026)Cite this article

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Abstract

KRAB zinc-finger proteins (KZFPs) are the most abundant family of DNA-binding proteins in humans and primarily induce the epigenetic silencing of transposable elements. While KZFPs use this ability to control the transposition potential of transposable elements, they can also act as epigenetic switches that gate transposable element-derived cis-regulatory modules in a cell context-specific manner. In this way, they participate in the domestication of mobile elements, expanding their ability to establish complex gene regulatory networks. In this Perspective, we discuss emerging evidence that mutations in KZFP genes can explain human disorders and that there is a need to understand the effect of mutations in their transposable element targets. We argue that increased focus on this large yet historically understudied family will greatly contribute to addressing gaps in our understanding of cell lineage specification during development, human phenotypes and related pathologies.

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Fig. 1: KZFPs are the largest family of DNA-binding proteins in the human genome and function to silence TEs.
Fig. 2: KZFPs have evolved rapidly in tetrapods and differ greatly between humans and mice.
Fig. 3: KZFPs facilitate the domestication of TEs.

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Acknowledgements

We would like to thank all members of the Imbeault group, past and present, for insightful discussions over the years. The group is funded by the Wellcome Trust Collaborative Award in Science (224600/Z/21/Z).

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Authors and Affiliations

  1. Department of Genetics, University of Cambridge, Cambridge, UK

    Juliette Davis, Diana Voicu, Urvashi Chitnavis & Jeremi Jaksina

  2. Department of Medical and Molecular Genetics, King’s College London, London, UK

    Michael Imbeault

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  1. Juliette Davis
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All authors (J.D., D.V., U.C., J.J. and M.I.) contributed substantially to the discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission under the leadership of the first (J.D.) and last (M.I.) authors.

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Supplementary Tables

Supplementary Table 1. List of human protein-coding KZFPs, including genomic location (GRCh38), domain configuration, number of zinc-fingers and zinc-finger signature of DNA-contacting amino acids. Supplementary Table 2. Calculated percentages of KZFP peaks overlapping different genomic categories used to produce Fig. 1c. Supplementary Table 3. Open Targets Platform data for KZFP–phenotype interactions with scores ≥0.5, ordered by score. Data are annotated with the KZFP domain and evolutionary status classification from Supplementary Table 1. Supplementary Table 4. Clustered matrix of Open Targets Platform data for KZFP–phenotype interactions with scores.

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Davis, J., Voicu, D., Chitnavis, U. et al. The role of KRAB zinc-finger proteins in expanding the domestication potential of transposable elements. Nat Genet (2026). https://doi.org/10.1038/s41588-025-02498-3

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