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An intersectional expression platform for gene complementation using RNA-fragment end joining (REJ)

Bachmann, L. C.; Hsu, R. H.; Hermann, K. J.; Williams, C. E.; Farman, R. L.; Criales, N.; Clark, C.; Kramer, S.; Thorn Perez, C.; Randles, S.; Lettieri, K.; Pfaff, S. L.

2026-09-14 molecular biology
10.64898/2026.09.13.751279 bioRxiv
Show abstract

Gene complementation is a powerful tool for genetic selection and protein functional studies but typically requires extensive screening for complementary components. Here we engineered a platform for gene complementation based on RNA end-joining (REJ) that precisely and efficiently splices separate RNA units into functional coding mRNAs. REJ is mediated by short structured modular RNA segments of ~250bp that: (a) promote RNA::RNA interaction, (b) coopt the intrinsic cell splicing machinery to facilitate RNA trans-splicing, (c) minimizes translation of protein fragments from un-spliced RNA segments, and (d) encodes scar-free protein. We demonstrate that REJ is a broadly applicable system that can reliably split nearly any gene into complementary segments regardless of protein structure. To enable the use of this system we provide a toolbox of reporters and a web-based design tool to facilitate vector design. Demonstrated REJ applications include genetic complementation, intersectional labeling of cell types, and efficient expression of large proteins.

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