Discovery and protein language model-guided design of hyperactive transposases
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.
Authors
- Ravi Das
- Noelia Ferruz (ORCID: https://orcid.org/0000-0003-4172-8201)
- Jonathan Lindstrom-Vautrin (ORCID: https://orcid.org/0000-0001-8132-424X)
- Jessica Jaraba-Wallace (ORCID: https://orcid.org/0000-0003-2950-9874)
- Dimitrije Ivančić
- Marc Güell (ORCID: https://orcid.org/0000-0003-4000-7912)
- Avencia Sánchez-Mejías (ORCID: https://orcid.org/0000-0002-9569-7853)
- Jorge Herrero-Vicente (ORCID: https://orcid.org/0000-0001-9605-2427)
- Marta Sanvicente-García (ORCID: https://orcid.org/0000-0002-4508-2834)
- Maria Gallo (ORCID: https://orcid.org/0000-0001-9099-7235)
- Paolo Petazzi
- Alejandro Agudelo
- Alejandro Ragel
- Irene Higueras
- Federico Billeci
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universitat Pompeu Fabra (ES)
- Parc de Salut (ES)
- Centre for Genomic Regulation (ES)
- Highlight Therapeutics (Spain) (ES)
- Instituto Valenciano de Investigaciones Económicas (ES)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s41587-025-02816-4
- Citations
- 5
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 8.75
Funders
- Universitat Pompeu Fabra
- European Commission
- Centro para el Desarrollo Tecnológico Industrial