A genome-wide analysis of Cas9 binding specificity using ChIP-seq and targeted sequence capture
Open accessPublished version of a preprint
Abstract
Clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided nucleases have gathered considerable excitement as a tool for genome engineering. However, questions remain about the specificity of target site recognition. Cleavage specificity is typically evaluated by low throughput assays (T7 endonuclease I assay, target amplification followed by high-throughput sequencing), which are limited to a subset of potential off-target sites. Here, we used ChIP-seq to examine genome-wide CRISPR binding specificity at gRNA-specific and gRNA-independent sites for two guide RNAs. RNA-guided Cas9 binding was highly specific to the target site while off-target binding occurred at much lower intensities. Cas9-bound regions were highly enriched in NGG sites, a sequence required for target site recognition by Streptococcus pyogenes Cas9. To determine the relationship between Cas9 binding and endonuclease activity, we applied targeted sequence capture, which allowed us to survey 1200 genomic loci simultaneously including potential off-target sites identified by ChIP-seq and by computational prediction. A high frequency of indels was observed at both target sites and one off-target site, while no cleavage activity could be detected at other ChIP-bound regions. Our results confirm the high-specificity of CRISPR endonucleases and demonstrate that sequence capture can be used as a high-throughput genome-wide approach to identify off-target activity.
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sgRNA-independent off-target effects also exist, urging unbiased experimental detection and validation.
“Nevertheless, accumulative studies have proved that sgRNA-independent off-target effects also exist, urging unbiased experimental detection and validation (Richter et al., 2020; O'Geen et al., 2015).”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as O'Geen et al., 2015
The Results section, “ChIP-seq identifies gRNA-specific and gRNA-independent binding sites” (page unavailable), reports 150 Cas9 binding sites common to two gRNAs. But the Results section on sequence capture reports no significant indel difference between untreated cells and cells given Cas9 with an empty gRNA; it identifies cleavage at only one off-target site. The Introduction and Discussion support broader detection and validation of off-target activity, but the paper does not establish sgRNA-independent off-target cleavage effects. (LLM, conf=0.88)
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- Authors
- O'Geen, H., Henry, I. M., Bhakta, M. S., Meckler, J. F., & Segal, D. J.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Segal, David J.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-20
- Volume
- 43
- Issue
- 6
- Pages
- 3389-3404
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC4381059
- OpenAlex
- W2150690792
- Cited by
- 219
- References
- 53
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 14 · 2023: 9 · 2022: 23 · 2021: 15 · 2020: 19 · 2019: 26 · 2018: 20 · 2017: 26 · 2016: 33 · 2015: 13 · 2014: 2 · 2013: 1
- FWCI
- 13.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Energy
- W. M. Keck Foundation
- National Institutes of Health (1c06rr012088-01, 1s10rr012964-01)
- Office of Science
- University of California, Davis
- National Heart, Lung, and Blood Institute (HL-086350, T32HL086350)
- National Human Genome Research Institute (R21HG006761, HG006761)
- National Cancer Institute (CA0933730)
- National Institute of General Medical Sciences (GM097073, R01GM097073)
- National Center for Research Resources (RR 026825, RR12964, S10RR026825, RR12088)
- Biological and Environmental Research
- Genome Center, University of California, Davis
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- CRISPR/Cas9, off-target binding, SpCas9, targeted sequence capture, indels, endonuclease activity, genome editing
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Animals, Bacterial Proteins, Base Sequence, Binding Sites, Cell Line, Streptococcus pyogenes, Mice, INDEL Mutation, Genome-Wide Association Study, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Associated Proteins
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