Transcriptome Engineering with RNA-Targeting Type VI-D CRISPR Effectors
Open accessAbstract
Class 2 CRISPR-Cas systems endow microbes with diverse mechanisms for adaptive immunity. Here, we analyzed prokaryotic genome and metagenome sequences to identify an uncharacterized family of RNA-guided, RNA-targeting CRISPR systems that we classify as type VI-D. Biochemical characterization and protein engineering of seven distinct orthologs generated a ribonuclease effector derived from Ruminococcus flavefaciens XPD3002 (CasRx) with robust activity in human cells. CasRx-mediated knockdown exhibits high efficiency and specificity relative to RNA interference across diverse endogenous transcripts. As one of the most compact single-effector Cas enzymes, CasRx can also be flexibly packaged into adeno-associated virus. We target virally encoded, catalytically inactive CasRx to cis elements of pre-mRNA to manipulate alternative splicing, alleviating dysregulated tau isoform ratios in a neuronal model of frontotemporal dementia. Our results present CasRx as a programmable RNA-binding module for efficient targeting of cellular RNA, enabling a general platform for transcriptome engineering and future therapeutic development.
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RfxCas13d can process a CRISPR array into multiple mature CRISPR RNAs.
“Notably, RfxCas13d is also capable of processing a CRISPR array into multiple mature CRISPR RNAs (crRNAs)10, presenting an attractive option for combinatorial perturbations at the RNA level.”
From Efficient combinatorial targeting of RNA transcripts in single cells with Cas13 RNA Perturb-seq (2023) · cites this paper as [10]
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Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies
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Optimization of specific RNA knockdown in mammalian cells with CRISPR-Cas13
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- Authors
- Konermann, S., Lotfy, P., Brideau, N. J., Oki, J., Shokhirev, M. N., & Hsu, P. D.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Hsu, Patrick D.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 173
- Issue
- 3
- Pages
- 665-676.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5910255
- OpenAlex
- W2793359586
- Cited by
- 1,164
- References
- 69
- Citations by year
- 2026: 106 · 2025: 130 · 2024: 197 · 2023: 159 · 2022: 164 · 2021: 158 · 2020: 136 · 2019: 69 · 2018: 44
- FWCI
- 36.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DP5OD021369)
- National Institute on Aging (R21AG056811)
- National Cancer Institute (P30CA014195)
- National Institute of General Medical Sciences (R01GM132465, R01GM131073)
- National Institute of Neurological Disorders and Stroke (P30NS072031)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- RNA-targeting CRISPR, RNA-guided RNA cleavage, alternative splicing, tau isoforms, frontotemporal dementia, adeno-associated virus delivery, Ruminococcus flavefaciens, RNA interference, prokaryotic adaptive immunity
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Animals, Bacterial Proteins, Cell Differentiation, Escherichia coli, Genetic Engineering, Humans, RNA, Protein Engineering, Lentivirus, Alternative Splicing, Sequence Analysis, RNA, Computational Biology, Gene Expression Profiling, RNA Interference, Ruminococcus, Mice, Induced Pluripotent Stem Cells, HEK293 Cells, Transcriptome, CRISPR-Cas Systems
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