Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation
Open accessAbstract
The bacterial CRISPR-Cas9 system has emerged as a multifunctional platform for sequence-specific regulation of gene expression. This Review describes the development of technologies based on nuclease-deactivated Cas9, termed dCas9, for RNA-guided genomic transcription regulation, both by repression through CRISPR interference (CRISPRi) and by activation through CRISPR activation (CRISPRa). We highlight different uses in diverse organisms, including bacterial and eukaryotic cells, and summarize current applications of harnessing CRISPR-dCas9 for multiplexed, inducible gene regulation, genome-wide screens and cell fate engineering. We also provide a perspective on future developments of the technology and its applications in biomedical research and clinical studies.
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One general challenge for these CRISPR methods involves the specificity and efficiency of gRNAs.
“One general challenge for these CRISPR methods involves the specificity and efficiency of gRNAs (reviewed in [94]).”
From Mapping gene regulatory networks from single-cell omics data (2018) · cites this paper as [94]
Because all four methods are based on CRISPR/CAS9, in principle any CRISPR-based perturbations could be used, including knockouts and transcriptional- or epigenetic-based repression or activation.
“As all four methods are based on CRISPR/CAS9, in principle, any CRISPR-based perturbations could be used, including knockouts and transcriptional- or epigenetic-based repression or activation (e.g. CRISPRi, CRISPRa [94]).”
From Mapping gene regulatory networks from single-cell omics data (2018) · cites this paper as [94]
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Specific Gene Repression by CRISPRi System Transferred through Bacterial Conjugation
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Self-citationEngineering synthetic TALE and CRISPR/Cas9 transcription factors for regulating gene expression
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Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors
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CRISPR–Cas9 Structures and Mechanisms
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CRISPR/Cas Genome Editing and Precision Plant Breeding in Agriculture
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“, VP64, p65AD, and VPR) can be used for gene regulation (26) (Figure 2c).”
BackgroundInduced pluripotent stem cell technology: a decade of progress.
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CRISPR/Cas9 in Genome Editing and Beyond
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Self-citationThe Post-GWAS Era: From Association to Function
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“Thus, genome editing technologies can also be used to validate potential CREs by altering epigenetic state, rather than the underlying DNA sequence.(66,67) A more recent study used CRISPR/Cas9 gene editing to investigate candidate causal variants at the SNCA locus,(68) which is associated with risk for Parkinson’s dis…”
BackgroundCRISPR/Cas9 therapeutics: progress and prospects
Li, T., Yang, Y., Qi, H., Cui, W., Zhang, L., Fu, X., He, X., Liu, M., Li, P., & Yu, T. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01309-7 · Cited by 770 · see citing works
“In addition, unlike CRISPR/ Cas9 gene editing, because the genome has not been modified, CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) are reversible, which greatly reduces the unknown problems caused by off-target effects.(143) Since the base sequence of DNA is not directly changed, the efficiency of…”
BackgroundDirected Evolution: Methodologies and Applications
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Regulation of gene expression by cis-acting long non-coding RNAs
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Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally
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Epigenetics and epigenomics in diabetic kidney disease and metabolic memory
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The interplay of epigenetic marks during stem cell differentiation and development
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CRISPR/Cas system: recent advances and future prospects for genome editing
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“The histone demethylase Lys-specific histone demethylase 1 (LSD1) fused to Neisseria meningitidis dCas9 has been used for experimentally controlling gene repression [92].”
BackgroundComparison of Cas9 activators in multiple species
Chavez, A., Tuttle, M. L., Pruitt, B. W., Ewen‐Campen, B., Chari, R., Ter‐Ovanesyan, D., Haque, S. J., Cecchi, R. J., Kowal, E. J. K., Buchthal, J., et al. (2016) · Nature Methods · doi:10.1038/nmeth.3871 · Cited by 508 · see citing works
Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing
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Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing
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Shifting paradigms in restoration of the world's coral reefs
van Oppen, M. J. H., Gates, R. D., Blackall, L. L., Cantin, N. E., Chakravarti, L. J., Chan, W. Y., Cormick, C., Crean, A. J., Damjanovic, K., Epstein, H. E., et al. (2017) · Global Change Biology · doi:10.1111/gcb.13647 · Cited by 441 · see citing works
Anti-CRISPR: discovery, mechanism and function
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Xu, Y., & Li, Z. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.08.031 · Cited by 424 · see citing works
“Then, by fusing transcriptional activators or repressors to dCas9, the CRISPRdCas9 system can be used to activate (CRISPRa) or inhibit (CRISPRi) transcription of target genes [37,38].”
MethodNaturally Occurring Off-Switches for CRISPR-Cas9
Pawluk, A., Amrani, N., Zhang, Y., Garcı́a, B., Hidalgo-Reyes, Y., Lee, J., Edraki, A., Shah, M. K., Sontheimer, E. J., Maxwell, K. L., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.017 · Cited by 384 · see citing works
Gene Editing and Crop Improvement Using CRISPR-Cas9 System
Arora, L., & Narula, A. (2017) · Frontiers in Plant Science · doi:10.3389/fpls.2017.01932 · Cited by 399 · see citing works
“…catalytic domains, HNH and RuvC) that fuses with general transcription factors to its C-termini (Figure 7). dCas9 has the ability to bind to specific target DNA guided by sgRNA and allows direct imaging and manipulation of transcription without altering the DNA sequence (Dominguez et al., 2016).”
BackgroundInfluentialAmino acids production focusing on fermentation technologies – A review
D’Este, M., Alvarado-Morales, M., & Angelidaki, İ. (2017) · Biotechnology Advances · doi:10.1016/j.biotechadv.2017.09.001 · Cited by 343 · see citing works
Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
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“Other CRISPR technologies, such as CRISPR activation, CRISPR repression, and orthogonal genetic manipulation will further empower the study of cancer immunotherapy with available and evolving toolkits (Dominguez et al., 2016; Esvelt et al., 2013; Gilbert et al., 2013; Thakore et al., 2016).”
Nguyen, D. N., Roth, T. L., Li, P. J., Chen, P. A., Apathy, R., Mamedov, M. R., Vo, L. T., Tobin, V. R., Goodman, D. B., Shifrut, E., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0325-6 · Cited by 315 · see citing works
“CRISPR-Cas9 interacts specifically with both genomic and non-genomic dsDNA 8 , and nuclease-inactive dCas9 has been used in many applications to localize protein and RNA effectors to specific DNA sequences without cleaving the target sequence 9 .”
Paixão, J. F. R., Gillet, F., Ribeiro, T. P., Bournaud, C., Lourenço‐Tessutti, I. T., Vasquez, D. D. N., de Melo, B. P., Engler, J. D. A., & Grossi‐de‐Sá, M. F. (2019) · Scientific Reports · doi:10.1038/s41598-019-44571-y · Cited by 310 · see citing works
From profiles to function in epigenomics
Stricker, S. H., Köferle, A., & Beck, S. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.138 · Cited by 290 · see citing works
Designing cell function: assembly of synthetic gene circuits for cell biology applications
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A compact, high-accuracy Cas9 with a dinucleotide PAM for in vivo genome editing
Edraki, A., Mir, A., Ibraheim, R., Gainetdinov, I., Yoon, Y., Song, C.-Q., Cao, Y., Gallant, J., Xue, W., Rivera-Pérez, J. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.12.003 · Cited by 265 · see citing works
“The availability of a catalytically dead version of Nme2Cas9 (dNme2Cas9) also promises to expand the scope of applications such as CRISPRi, CRISPRa, base editing, and related approaches (Dominguez et al., 2016; Komor et al., 2017).”
BackgroundMapping gene regulatory networks from single-cell omics data
Fiers, M. W. E. J., Minnoye, L., Aibar, S., Bravo González-Blas, C., Kalender Atak, Z., & Aerts, S. (2018) · Briefings in Functional Genomics · doi:10.1093/bfgp/elx046 · Cited by 235 · see citing works
Interrogation of enhancer function by enhancer-targeting CRISPR epigenetic editing
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Cas9 versus Cas12a/Cpf1: Structure–function comparisons and implications for genome editing
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Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein
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Kramer, N. J., Haney, M. S., Morgens, D. W., Jovičić, A., Couthouis, J., Li, A., Ousey, J., Ma, R., Bieri, G., Tsui, C. K., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0070-7 · Cited by 226 · see citing works
Regulatory Enhancer–Core-Promoter Communication via Transcription Factors and Cofactors
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Synthetic CRISPR-Cas gene activators for transcriptional reprogramming in bacteria
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The CRISPR Spacer Space Is Dominated by Sequences from Species-Specific Mobilomes
Shmakov, S., Sitnik, V., Makarova, K. S., Wolf, Y. I., Severinov, K., & Koonin, E. V. (2017) · mBio · doi:10.1128/mbio.01397-17 · Cited by 210 · see citing works
“…success of the Cas9 and later Cas12a (Cpf1) endonucleases as two of the new generation of genome editing, regulation, and interrogation tools (5–9), comparative genomics, structures, biochemical activities, and biological functions of CRISPR-Cas systems have been recently explored in…”
Targeted DNA methylation in vivo using an engineered dCas9-MQ1 fusion protein
Lei, Y., Zhang, X., Su, J., Jeong, M., Gundry, M. C., Huang, Y.-H., Zhou, Y., Li, W., & Goodell, M. A. (2017) · Nature Communications · doi:10.1038/ncomms16026 · Cited by 218 · see citing works
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Inducible and multiplex gene regulation using CRISPR–Cpf1-based transcription factors
Tak, Y. E., Kleinstiver, B. P., Nuñez, J. K., Hsu, J. Y., Horng, J. E., Gong, J., Weissman, J. S., & Joung, J. K. (2017) · Nature Methods · doi:10.1038/nmeth.4483 · Cited by 208 · see citing works
The functions of long noncoding RNAs in development and stem cells
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“…catalytically inactive CRISPR/Cas9 system (dCas9) have the potential of harnessing the targeting specificity of CRISPR without altering the genome (Dominguez et al., 2016), but they still may have lncRNAunrelated effects on chromatin, in particular when the dCas9 is coupled with a…”
BackgroundEngineering biological systems using automated biofoundries
Chao, R., Mishra, S., Si, T., & Zhao, H. (2017) · Metabolic Engineering · doi:10.1016/j.ymben.2017.06.003 · Cited by 201 · see citing works
CRISPR Cpf1 proteins: structure, function and implications for genome editing
Safari, F., Zare, K., Negahdaripour, M., Barekati‐Mowahed, M., & Ghasemi, Y. (2019) · Cell & Bioscience · doi:10.1186/s13578-019-0298-7 · Cited by 196 · see citing works
“Modulation of endogenous genes by ddCpf1‐mediated technology In addition to the usage of CRISPR system for genome editing, this technology can be used as a sequence-specific, non-mutagenic gene regulation strategy [73].”
MethodGene editing and CRISPR in the clinic: current and future perspectives
Hirakawa, M. P., Krishnakumar, R., Timlin, J. A., Carney, J. P., & Butler, K. S. (2020) · Bioscience Reports · doi:10.1042/bsr20200127 · Cited by 197 · see citing works
A CRISPR toolbox to study virus–host interactions
Puschnik, A. S., Majzoub, K., Ooi, Y. S., & Carette, J. E. (2017) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2017.29 · Cited by 183 · see citing works
High-Level dCas9 Expression Induces Abnormal Cell Morphology in Escherichia coli
Cho, S., Choe, D., Lee, E., Kim, S. C., Palsson, B. Ø., & Cho, B. (2018) · ACS Synthetic Biology · doi:10.1021/acssynbio.7b00462 · Cited by 185 · see citing works
Spatiotemporal control of CRISPR/Cas9 gene editing
Zhuo, C., Zhang, J., Lee, J., Jiao, J., Cheng, D., Liu, L., Kim, H., Tao, Y., & Li, M. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00645-w · Cited by 196 · see citing works
“GENETIC REGULATION CRISPR/Cas9 technology provides a diversified sequence-specific gene regulation “tool kit” by using catalytically impaired Cas9 (dCas9), which does not cleave DNA but can precisely and specifically bind DNA under the guidance of specific sgRNA.(36) Therefore, dCas9 can be designed to recruit differe…”
BackgroundMethodRecent progress in genetically modified microalgae for enhanced carbon dioxide sequestration
Barati, B., Zeng, K., Baeyens, J., Wang, S., Addy, M., Gan, S. Y., & Abomohra, A. (2020) · Biomass and Bioenergy · doi:10.1016/j.biombioe.2020.105927 · Cited by 187 · see citing works
Human pluripotent reprogramming with CRISPR activators
Weltner, J., Balboa, D., Katayama, S., Bespalov, M., Krjutškov, K., Jouhilahti, E.-M., Trokovic, R., Kere, J., & Otonkoski, T. (2018) · Nature Communications · doi:10.1038/s41467-018-05067-x · Cited by 181 · see citing works
Precision genome editing in the CRISPR era
Salsman, J., & Dellaire, G. (2016) · Biochemistry and Cell Biology · doi:10.1139/bcb-2016-0137 · Cited by 183 · see citing works
Epigenetics of Alzheimer’s Disease
Perković, M. N., Paska, A. V., Konjevod, M., Kouter, K., Štrac, D. Š., Erjavec, G. N., & Pivac, N. (2021) · Biomolecules · doi:10.3390/biom11020195 · Cited by 181 · see citing works
“The mutant form of the Cas9, called dead Cas9 (dCas9), advanced the CRISPR/Cas9 gene editing tool and resulted in CRISPR interference (CRISPRi) technology, when dCas9 is fused or interacts with transcriptional repressors, and in CRISPR activation (CRISPRa) technology, when dCas9 is fused or interacts with transcriptio…”
BackgroundMultidimensional chemical control of CRISPR–Cas9
Maji, B., Moore, C. L., Zetsche, B., Volz, S. E., Zhang, F., Shoulders, M. D., & Choudhary, A. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2224 · Cited by 175 · see citing works
Inhibition Mechanism of an Anti-CRISPR Suppressor AcrIIA4 Targeting SpyCas9
Yang, H., & Patel, D. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.024 · Cited by 178 · see citing works
“Besides, a catalytically dead mutant, SpyCas9 (dSpyCas9, D10A/H840A) hasservedasaneffective andspecificRNA-guided genome-binding platform (Dominguez et al., 2016; Qi et al., 2013; Wang et al., 2016a).”
RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors
Thakore, P. I., Kwon, J. B., Nelson, C. E., Rouse, D. C., Gemberling, M. P., Oliver, M. L., & Gersbach, C. A. (2018) · Nature Communications · doi:10.1038/s41467-018-04048-4 · Cited by 173 · see citing works
CRISPR–Cas9-based photoactivatable transcription systems to induce neuronal differentiation
Nihongaki, Y., Furuhata, Y., Otabe, T., Hasegawa, S., Yoshimoto, K., & Sato, M. (2017) · Nature Methods · doi:10.1038/nmeth.4430 · Cited by 175 · see citing works
Duchenne muscular dystrophy: disease mechanism and therapeutic strategies
Angulski, A. B. B., Hosny, N., Cohen, H., Martin, A. A., Hahn, D., Bauer, J., & Metzger, J. M. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1183101 · Cited by 184 · see citing works
“This approach enables single-base transitions or transversions, as well as site-specific genomic insertions and deletions, without introducing DSBs or the need for an exogenous donor DNA as a template for HDR repair.”
BackgroundInfluentialHuang, C.-H., Shen, C. R., Li, H., Sung, L.-Y., Wu, M.-Y., & Hu, Y.-C. (2016) · Microbial Cell Factories · doi:10.1186/s12934-016-0595-3 · Cited by 164 · see citing works
“This new technology, termed CRISPR interference (CRISPRi), was recently repurposed to repress sequence-specific genes in diverse eucaryotic and procaryotic cells, for rewiring metabolic networks [23, 24] and high-throughput interrogation of genome-wide gene functions [25, 26].”
MethodRaschmanová, H., Weninger, A., Glieder, A., Kovar, K., & Vogl, T. J. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.01.006 · Cited by 164 · see citing works
Titrating gene expression using libraries of systematically attenuated CRISPR guide RNAs
Jost, M., Santos, D. A., Saunders, R. A., Horlbeck, M. A., Hawkins, J. S., Scaria, S. M., Norman, T. M., Hussmann, J. A., Liem, C. R., Gross, C. A., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-019-0387-5 · Cited by 164 · see citing works
Sanborn, A. L., Yeh, B. T., Feigerle, J. T., Hao, C. V., Townshend, R. J. L., Aiden, E. L., Dror, R. O., & Kornberg, R. D. (2021) · eLife · doi:10.7554/elife.68068 · Cited by 158 · see citing works
Simultaneous repression of multiple bacterial genes using nonrepetitive extra-long sgRNA arrays
Reis, A. C., Halper, S. M., Vezeau, G. E., Cetnar, D. P., Hossain, A., Clauer, P. R., & Salis, H. M. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0286-9 · Cited by 157 · see citing works
Exploring the potential of genome editing CRISPR-Cas9 technology
Singh, V., Braddick, D., & Dhar, P. K. (2016) · Gene · doi:10.1016/j.gene.2016.11.008 · Cited by 164 · see citing works
“The primary disadvantage of this system is that it may repress downstream genes within an operon instead of an isolated targeted gene (Dominguez et al., 2016).”
BackgroundInfluentialAdvances in Engineering the Fly Genome with the CRISPR-Cas System
Bier, E., Harrison, M. M., O’Connor-Giles, K. M., & Wildonger, J. (2018) · Genetics · doi:10.1534/genetics.117.1113 · Cited by 155 · see citing works
CRISPR interference-based specific and efficient gene inactivation in the brain
Zheng, Y., Shen, W., Zhang, J., Yang, B., Liu, Y., Qi, H., Yu, X., Lu, S., Chen, Y., Xu, Y., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0077-5 · Cited by 157 · see citing works
C-BERST: defining subnuclear proteomic landscapes at genomic elements with dCas9–APEX2
Gao, X. D., Tu, L., Mir, A., Rodríguez, T., Ding, Y., Leszyk, J., Dekker, J., Shaffer, S. A., Zhu, L. J., Wolfe, S. A., et al. (2018) · Nature Methods · doi:10.1038/s41592-018-0006-2 · Cited by 153 · see citing works
Shao, J., Wang, M., Yu, G., Zhu, S., Yu, Y., Heng, B. C., Wu, J., & Ye, H. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802448115 · Cited by 154 · see citing works
CRISPR-Cas9/Cas12a biotechnology and application in bacteria
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The Caenorhabditis elegans Transgenic Toolbox
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“This is likely due to poor gene induction with only one of the guide RNAs in an individual cell; previous work has shown that multiple sgRNAs per gene are more efficient at inducing expression (Dominguez et al., 2016).”
BackgroundEngineering Nanoparticles for Targeted Delivery of Nucleic Acid Therapeutics in Tumor
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“In addition to permanently altering endogenous gene sequences, CRISPR/Cas9 can regulate the activity of genes through promoter modulation, an approach known as CRISPR activation (CRISPRa) (Dominguez et al., 2016; Liao et al., 2017; Matharu et al., 2019).”
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“These poor overlaps may reflect the potential dependency of CRISPRi off-target effects on the cell type, the epigenetic landscape, or other factors (56).”
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BackgroundThe NIH Somatic Cell Genome Editing program
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NmeCas9 is an intrinsically high-fidelity genome-editing platform
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“In addition to genome editing, 101 catalytically inactivated Cas9 (“dead” Cas9, dCas9) retains its sgRNA-guided DNA binding function, 102 enabling fused or tethered functionalities to be delivered to precise genomic loci [25, 26].”
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Engineering disease resistant plants through CRISPR-Cas9 technology
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Harnessing CRISPR/Cas systems for programmable transcriptional and post-transcriptional regulation
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“Unlike ZFs and TALE-based transcriptional regulators, fusing dCas9 to effector domains such as transcriptional activators (CRISPRa) or repressors (CRISPRi) has enabled the repurposing of the system for scalable and robust transcriptome manipulation (Dominguez et al., 2016).”
BackgroundPrecision Control of CRISPR-Cas9 Using Small Molecules and Light
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- Authors
- Dominguez, A. A., Lim, W. A., & Qi, L. S.
- Affiliations
- Stanford University (US)
- QB3 (US)
- Corresponding author
- Lim, Wendell A.
- Qi, Lei S.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2015-12-16
- Volume
- 17
- Issue
- 1
- Pages
- 5-15
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- PMC
- PMC4922510
- OpenAlex
- W2204875887
- Cited by
- 832
- References
- 91
- Citations by year
- 2026: 39 · 2025: 41 · 2024: 58 · 2023: 65 · 2022: 78 · 2021: 81 · 2020: 95 · 2019: 105 · 2018: 106 · 2017: 96 · 2016: 63 · 2015: 2 · 2014: 1 · 2013: 1
- FWCI
- 8.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DP5OD017887)
- National Institute on Drug Abuse (R01DA036858)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- CRISPR/Cas9, dCas9, CRISPR interference, CRISPR activation, gene expression inhibition, gene activation, genome-wide screen
- MeSH terms
- Animals, Humans, Models, Genetic, Transcription, Genetic, Genome, RNA Editing, Genomics, CRISPR-Cas Systems
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