2. Academic Validation
  3. Discovery and protein language model-guided design of hyperactive transposases

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

Affiliations

  • 1 Integra Therapeutics, Barcelona, Spain. dimitrie.ivancic@upf.edu.
  • 2 Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. dimitrie.ivancic@upf.edu.
  • 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. marc.guell@upf.edu.
  • 8 Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. marc.guell@upf.edu.
  • 9 ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. marc.guell@upf.edu.
  • # 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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