CRISPRs for Optimal Targeting: Delivery of CRISPR Components as DNA, RNA, and Protein into Cultured Cells and Single-Cell Embryos.

Authors:
Kouranova E, Forbes K, Zhao G, Warren J, Bartels A, Wu Y, Cui .
In:
Source: Hum Gene Ther
Publication Date: (2016)
Issue: 27(69: 464-75
Research Area:
Gene Expression
Regenerative medicine
Cells used in publication:
C6
Species: rat
Tissue Origin: brain
Neuro-2a [N2a]
Species: mouse
Tissue Origin: brain
Platform:
4D-Nucleofector® 96-well Systems
Experiment

All cell transfections were performed with a Nucleofector (Lonza) according to the manufacturer’s 96-well shuttle protocol for respective cell lines. After trypsinization, cells were counted, pelleted, and washed twice in Hanks balanced salt solution to minimize nuclease carryover from growth medium. Specifically, for the rat C6 cell line, SG solution and program FF-127 were used to transfect 200,000 cells. For the mouse Neuro-2a cell line, SF solution and program 96-DS-137 were used to transfect 200,000 cells per reaction. One microgram of a GFP plasmid was always transfected for each conditionas a control. ZFN mRNAs were tranfected at 2 µg/reaction. Regardless of the delivery method of Cas9 (plasmid, mRNA or protein), sgRNAs were used at 2–12 µg/reaction. Cas9 expression plasmid was transfected at 2 µg/reaction, Cas9 mRNA at 2–4 µg/reaction, and recombinant Cas9 protein at 3–10 µg/reaction.

Abstract

The rapid development of CRISPR technology greatly impacts the field of genetic engineering. The simplicity in design and generation of highly efficient CRISPR reagents allows more and more researchers to take on genome editing in different model systems in their own labs, even for those who found it daunting before. An active CRISPR complex contains a protein component (Cas9) and an RNA component (small guide RNA [sgRNA]), which can be delivered into cells in various formats. Cas9 can be introduced as a DNA expression plasmid, in vitro transcripts, or as a recombinant protein bound to the RNA portion in a ribonucleoprotein particle (RNP), whereas the sgRNA can be delivered either expressed as a DNA plasmid or as an in vitro transcript. Here we compared the different delivery methods in cultured cell lines as well as mouse and rat single-cell embryos and view the RNPs as the most convenient and efficient to use. We also report the detection of limited off-targeting in cells and embryos and discuss approaches to lower that chance. We hope that researchers new to CRISPR find our results helpful to their adaptation of the technology for optimal gene editing.