ArticleEpigenetics & chromatin2019
Ezh2-dCas9 and KRAB-dCas9 enable engineering of epigenetic memory in a context-dependent manner.
Article in Epigenetics & chromatin, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.
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Who cites it
106 citing papers in PubMed, 170 citations in OpenAlex.
- From epigenetic mark detection to rational design of epigenetic editing strategies.Molecular therapy. Advances · 2026Review
- Integrated epigenetic and genetic programming of primary human T cells.Nature biotechnology · 2026Article
- Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.Nature biotechnology · 2026Article
- Advances and clinical potential of epigenome editing.Cellular and molecular life sciences : CMLS · 2026Review
- Transcriptional interference drives intronic polyadenylation at the endogenous H13/Mcts2 locus.Nucleic acids research · 2026Article
- A Functionally Conserved Enhancer is Critical for PGC1A Expression and Thermogenesis in Brown Fat.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Focal Polycomb-Mediated Repression of Neuronal Identity and Synaptic Maintenance Genes in Aging Neurons.Cureus · 2026Article
- A combinatorial domain screening platform reveals epigenetic effector interactions for transcriptional perturbation.Nature communications · 2026Article
- The Future of Epigenetics: Emerging Technologies and Clinical Applications.ACS pharmacology & translational science · 2026Review
- Epigenetic editing: from concept to clinic.Nature reviews. Drug discovery · 2026Review
- A toolkit for programmable transcriptional engineering across eukaryotic kingdoms.bioRxiv : the preprint server for biology · 2026Article
- Advances and challenges of precision epigenetic therapy in treating genomic imprinting diseases.Translational pediatrics · 2026Review
- Deciphering the regulatory landscape of enhancer RNAs in health and disease.Signal transduction and targeted therapy · 2026Review
- Epigenome editing based treatment: Progresses and challenges.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- Pioneer Factor FOXA1 Boosts CHO Cell Productivity.Biotechnology journal · 2026Article
- KDM4D enhances radiosensitivity in esophageal squamous cell carcinoma through the SRBD1/RPL11/c-Myc/WIP1/CHK1 axis.American journal of translational research · 2026Article
- Exploring CRISPR-Cas: The transformative impact of gene editing in molecular biology.Molecular therapy. Nucleic acids · 2025Review
- Reversing transgene silencing via targeted chromatin editing.bioRxiv : the preprint server for biology · 2025Article
- Engineering Inducible Cell Fate Transitions by Harnessing Epigenetic Silencing.bioRxiv : the preprint server for biology · 2025Article
- Human opsin restoration by histone methylation using methyltransferase fusion protein SETD7-dCas9.Molecular therapy. Nucleic acids · 2025Article
46 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundRewriting of the epigenome has risen as a promising alternative to gene editing for precision medicine. In nature, epigenetic silencing can result in complete attenuation of target gene expression over multiple mitotic divisions. However, persistent repression has been difficult to achieve in a predictable manner using targeted systems.
resultsHere, we report that persistent epigenetic memory required both a DNA methyltransferase (DNMT3A-dCas9) and a histone methyltransferase (Ezh2-dCas9 or KRAB-dCas9). We demonstrate that the histone methyltransferase requirement can be locus specific. Co-targeting Ezh2-dCas9, but not KRAB-dCas9, with DNMT3A-dCas9 and DNMT3L induced long-term HER2 repression over at least 50 days (approximately 57 cell divisions) and triggered an epigenetic switch to a heterochromatic environment. An increase in H3K27 trimethylation and DNA methylation was stably maintained and accompanied by a sustained loss of H3K27 acetylation. Interestingly, substitution of Ezh2-dCas9 with KRAB-dCas9 enabled long-term repression at some target genes (e.g., SNURF) but not at HER2, at which H3K9me3 and DNA methylation were transiently acquired and subsequently lost. Off-target DNA hypermethylation occurred at many individual CpG sites but rarely at multiple CpGs in a single promoter, consistent with no detectable effect on transcription at the off-target loci tested. Conversely, robust hypermethylation was observed at HER2. We further demonstrated that Ezh2-dCas9 required full-length DNMT3L for maximal activity and that co-targeting DNMT3L was sufficient for persistent repression by Ezh2-dCas9 or KRAB-dCas9.
conclusionsThese data demonstrate that targeting different combinations of histone and DNA methyltransferases is required to achieve maximal repression at different loci. Fine-tuning of targeting tools is a necessity to engineer epigenetic memory at any given locus in any given cell type.
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