Epigenome editing strategies for the functional annotation of CTCF insulators

Tarjan, Daniel R.; Flavahan, William A.; Bernstein, Bradley E.

doi:10.1038/s41467-019-12166-w

Cited by 88CRISPR and Genetic EngineeringGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.

Epigenome editing strategies for the functional annotation of CTCF insulators

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Tarjan, Daniel R., Flavahan, William A., Bernstein, Bradley E.·2019·Nature Communications

DOI 10.1038/s41467-019-12166-wPMC PMC6751197

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Abstract

The human genome is folded into regulatory units termed ‘topologically-associated domains’ (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, partially-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing. Finally, we apply these strategies to simulate an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.

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CRISPRoff can perturb enhancers.
“Our initial experiments demonstrate CRISPRoff can perturb enhancers, opening the potential to target genome elements that control tissue-specific gene expression (Fulco et al., 2016; Tarjan et al., 2019).”
From Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing (2021) · cites this paper as Tarjan et al., 2019
In Results, under “Epigenome editing can disrupt CTCF at topological insulators” (page unavailable), the paper says dCas9-KRAB can repress enhancer function. Its experiments, however, target CTCF insulators, and our copy does not identify or test CRISPRoff as an enhancer-perturbing method. (LLM, conf=0.83)
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Authors: Tarjan, D. R., Flavahan, W. A., & Bernstein, B. E.
Affiliations: Broad Institute (US)
Corresponding author: Bernstein, Bradley E.
ORCID: Flavahan, William A.
Bernstein, Bradley E.
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2019-09-18
Volume: 10
Issue: 1
Pages: 4258-4258
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/s41467-019-12166-w
PMC: PMC6751197
OpenAlex: W2974053118
Cited by: 88
References: 37
Citations by year: 2026: 7 · 2025: 15 · 2024: 15 · 2023: 9 · 2022: 14 · 2021: 14 · 2020: 11 · 2019: 3
FWCI: 3.47
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
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)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: U.S. Department of Health & Human Services | NIH | National Cancer Institute (DP1CA216873)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords: topologically associating domains, epigenome editing, dCas9, DNMT3A, DNA methylation, chromatin looping, enhancer-gene interactions, brain tumorigenesis, genome organization, transcriptional repression
MeSH terms: Gene Editing, CCCTC-Binding Factor, CRISPR-Associated Protein 9, DNA Methyltransferase 3A, Brain Neoplasms, Cell Line, DNA (Cytosine-5-)-Methyltransferases, Humans, Promoter Regions, Genetic, Recombinant Fusion Proteins, Repressor Proteins, Genome, Human, DNA Methylation, Epigenesis, Genetic, HEK293 Cells, Carcinogenesis, CRISPR-Cas Systems

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Epigenome editing strategies for the functional annotation of CTCF insulators

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