Discovery and protein language model-guided design of hyperactive transposases

  • Nat Biotechnol. 2025 Oct 2. doi: 10.1038/s41587-025-02816-4.
Dimitrije Ivančić  #  1  2 ,  Alejandro Agudelo  #  3  4 ,  Jonathan Lindstrom-Vautrin  3 ,  Jessica Jaraba-Wallace  3 ,  Maria Gallo  3 ,  Ravi Das  3 ,  Alejandro Ragel  3 ,  Jorge Herrero-Vicente  3 ,  Irene Higueras  4 ,  Federico Billeci  3 ,  Marta Sanvicente-García  3 ,  Paolo Petazzi  3 ,  Noelia Ferruz  5  6 ,  Avencia Sánchez-Mejías  3 ,  Marc Güell  7  8  9
Affiliations
  • 1. Integra Therapeutics, Barcelona, Spain. [email protected].
  • 2. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. [email protected].
  • 3. Integra Therapeutics, Barcelona, Spain.
  • 4. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
  • 5. Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 6. Universitat Pompeu Fabra, Barcelona, Spain.
  • 7. Integra Therapeutics, Barcelona, Spain. [email protected].
  • 8. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. [email protected].
  • 9. ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. [email protected].
  • # Contributed equally.
PMID: 41039042 DOI: 10.1038/s41587-025-02816-4
Abstract

The diversity and biochemical potential of the PiggyBac transposase gene insertion system remains largely unexplored. Using a eukaryotic transposon mining pipeline, we expand the explored diversity by two orders of magnitude and experimentally validate a subset of highly divergent PiggyBac sequences. Fine-tuning a protein language model to further expand PiggyBac sequence space discovers transposases with improved activity and that are compatible with T cell engineering and Cas9-directed transposase-assisted integration.

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