CRISPR-Cas12a nucleases function with structurally engineered crRNAs: SynThetic trAcrRNA

Authors:
Jedrzejczyk DJ, Poulsen LD, Mohr M, Damas ND, Schoffelen S, Barghetti A, Baumgartner R, Weinert BT, Warnecke T, Gill RT
In:
Source: Biosci Rep
Publication Date: (2022)
Issue: 12(1): 12193
Research Area:
Immunotherapy / Hematology
Basic Research
Molecular Biology
Cells used in publication:
Jurkat
Species: human
Tissue Origin: blood
Platform:
4D-Nucleofector® 96-well Systems
Experiment

Cells were grown at 37 °C in 5% CO2 incubators at a density of 0.5–1.5 × 10^6 cells/mL and passaged at 0.1 × 10^6 cell/mL 24-h before electroporation. For electroporation, cells were harvested by centrifugation (200 × g, RT, 5 min) and resuspended at 10 × 10^6 cells/mL (2 × 10^5 cells/20 µL) in supplemented SF nucleofection buffer (Lonza). Cell culture media supernatant was periodically tested for mycoplasma contamination using the MycoAlert PLUS mycoplasma detection kit (Lonza).

4D Nucleofector with Shuttle unit (V4SC-2960 Nucleocuvette Strips) was used for electroporation, following the manufacturer’s instructions. Jurkat cells were electroporated using the SF Cell Line Nucleofector X Kit (Lonza), CA-137 program, with 2 × 10^5 cells in 20 µL SF buffer for each nucleofection reaction. The cell suspension was mixed with RNPs, immediately transferred to the nucleocuvette, and subjected to nucleofection in the 96-well Shuttle device. Cells were immediately re-suspended in the cultivation medium and plated on 96-well, flat-bottom, non-cell culture treated plates (Falcon).

Abstract

CRISPR-Cas12a systems are becoming an attractive genome editing tool for cell engineering due to their broader editing capabilities compared to CRISPR-Cas9 counterparts. As opposed to Cas9, the Cas12a endonucleases are characterized by a lack of trans-activating crRNA (tracrRNA), which reduces the complexity of the editing system and simultaneously makes CRISPR RNA (crRNA) engineering a promising approach toward further improving and modulating editing activity of the CRISPR-Cas12a systems. Here, we design and validate sixteen types of structurally engineered Cas12a crRNAs targeting various immunologically relevant loci in-vitro and in-cellulo. We show that all our structural modifications in the loop region, ranging from engineered breaks (STAR-crRNAs) to large gaps (Gap-crRNAs), as well as nucleotide substitutions, enable gene-cutting in the presence of various Cas12a nucleases. Moreover, we observe similar insertion rates of short HDR templates using the engineered crRNAs compared to the wild-type crRNAs, further demonstrating that the introduced modifications in the loop region led to comparable genome editing efficiencies. In conclusion, we show that Cas12a nucleases can broadly utilize structurally engineered crRNAs with breaks or gaps in the otherwise highly-conserved loop region, which could further facilitate a wide range of genome editing.