Locus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC
Open accessAbstract
Efforts to manipulate locus-specific histone acetylation to assess their causal role in gene expression and cellular and behavioural phenotypes have been impeded by a lack of experimental tools. The Cas9 nuclease has been adapted to target epigenomic modifications, but a detailed description of the parameters of such synthetic epigenome remodellers is still lacking. Here we describe a Cas9-based histone deacetylase (HDAC) and the design principles required to achieve locus-specific histone deacetylation. We assess its range of activity and specificity, and analyse target gene expression in two different cell types to investigate cellular context-dependent effects. Our findings demonstrate that the chromatin environment is an important element to consider when utilizing this synthetic HDAC.
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Additional dCas9-tethered domains have been shown to disrupt enhancer activity.
“Additional dCas9-tethered domains have been shown to disrupt enhancer activity (e.g. histone demethylase LSD1210, histone deacetylase 3211, and DNA methylators MQ212 or DNMT3A213-215), and could potentially be adapted to large-scale screens.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [211]
The Results show that dCas9-HDAC3 can reduce gene expression when targeted appropriately at promoters. The Discussion explicitly says future work is needed to determine whether it can affect gene expression when positioned at enhancers, contrary to the claim that enhancer disruption had been shown. (LLM, conf=0.87)
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- Authors
- Kwon, D. Y., Zhao, Y.-T., Lamonica, J. M., & Zhou, Z.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Zhou, Zhaolan
- Venue
- Nature Communications
- Published
- 2017-05-12
- Volume
- 8
- Issue
- 1
- Pages
- 15315-15315
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5437308
- OpenAlex
- W2612830428
- Cited by
- 246
- References
- 34
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 31 · 2023: 22 · 2022: 37 · 2021: 29 · 2020: 27 · 2019: 32 · 2018: 26 · 2017: 8
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Brain Research Foundation
- University of Pennsylvania
- National Institutes of Health
- Perelman School of Medicine, University of Pennsylvania
- National Institute of Mental Health (R56MH111719, R01MH111719, R01MH091850)
- National Institute of Neurological Disorders and Stroke (T32NS007413)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- histone deacetylation, CRISPR/Cas9, histone acetylation, chromatin environment, gene expression regulation
- MeSH terms
- Histone Deacetylase 3, Acetylation, Animals, Chromatin, Gene Expression Regulation, Histone Deacetylases, Histones, Humans, Promoter Regions, Genetic, Gene Expression Profiling, Cell Line, Tumor, Mice, Genetic Loci, HEK293 Cells, Epigenomics, CRISPR-Cas Systems
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