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Editing DNA Methylation in the Mammalian Genome
Open accessAbstract
Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.
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“CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) employ catalytically deactivated forms of Cas9 (dCas9) that are fused to transcriptional repressors or activators 29,101 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [101]
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“They are currently being evaluated in preclinical models of PTSD, addiction, and MDD (125, 126).”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [125]
Experimental — accuracy not yet measuredIn the citing paper
“dCas9-TET and dCas9-DNMT3a fusions have been shown to induce effective remodeling of 5mC (Fig. 3) (56).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [56]
In the citing paper
“Similarly, targeted de-methylation with a dCas9-TET fusion protein has been demonstrated (Amabile et al., 2016; Liu et al., 2016), and this strategy could be used to restore an insulated neighborhood whose anchor site is disrupted by aberrant DNA methylation (Figure 8B).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Liu et al., 2016
In the citing paper
“Indeed, targeted methylation of a neighborhood anchor site with a dCas9-DNA-metyltransferase-3 fusion protein has been shown to disrupt the neighborhood (Figure 8A) (Liu et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Liu et al., 2016
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“, 2018) or local manipulation of DNA or histone modifications (Hilton et al., 2015; Kearns et al., 2015; Lei et al., 2017; Liu et al., 2016; Vojta et al., 2016; Xu et al., 2016).”
BackgroundGenome Editing in Plants: Exploration of Technological Advancements and Challenges
Vats, S., Kumawat, S., Kumar, V., Patil, G., Joshi, T., Sonah, H., Sharma, T. R., & Deshmukh, R. K. (2019) · Cells · doi:10.3390/cells8111386 · Cited by 195
“CRISPR/Cas mediated methylation and demethylation has already been achieved in the animal system [151].”
BackgroundPflueger, C., Tan, D., Swain, T., Nguyen, T., Pflueger, J., Nefzger, C., Polo, J. M., Ford, E., & Lister, R. (2018) · Genome Research · doi:10.1101/gr.233049.117 · Cited by 188
“Previous work has highlighted the ability of dCas9 to be used to induce DNA methylation at desired regions in the genome(Vojta et al. 2016; Amabile et al. 2016; Liu et al. 2016; Lei et al. 2017; Stepper et al. 2017).”
BackgroundMethodInfluentialDynamics and Context-Dependent Roles of DNA Methylation
Ambrosi, C. M., Manzo, M., & Baubec, T. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.02.008 · Cited by 201
Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism
Tran, N. Q. V., & Miyake, K. (2017) · International Journal of Genomics · doi:10.1155/2017/7526592 · Cited by 189
Development of CRISPR-Cas systems for genome editing and beyond
Zhang, F. (2019) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583519000052 · Cited by 188
“…the dosage of Cas9 in cells, it is also possible to engineer Cas9 so that its nuclease activity becomes drugor light-inducible (Davis et al., 2015; Nihongaki et al., 2015; Truong et al., 2015; Wright et al., 2015; Zetsche et al., 2015b; Liu et al., 2016a; Nguyen et al., 2016; Rose et al., 2017).”
BackgroundMethodInfluentialEpigenetics 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 192
Li, C., Brant, E. J., Budak, H., & Zhang, B. (2021) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2100009 · Cited by 191
“By fusing dCas9 to a catalytic domain of DNMT, such as DNMT3 or MQ3, CRISPR/Cas systems have successfully targeted methylation to specific sites in both plants and ani‐ mals (Liu et al., 2016; Vojta et al., 2016; Lau and Suh, 2018).”
BackgroundMethodDrug delivery systems for CRISPR-based genome editors
Madigan, V. J., Zhang, F., & Dahlman, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00762-x · Cited by 193
“Although use of dCas9 alone can reduce target gene transcription by preventing passage of RNA polymerase, fusion of dCas9 with transcriptional repressors, such as the Krüppel-associated box domain 18 , or epigenome modifiers, such as DNA methylase DNMT3A 19,20 , has afforded the generation of CRISPR interference syste…”
BackgroundCRISPR/dCas9 Tools: Epigenetic Mechanism and Application in Gene Transcriptional Regulation
Cai, R., Lv, R., Shi, X., Yang, G., & Jin, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914865 · Cited by 189
“Liu et al. [57] targeted methylation of CTCF rings using dCas9-DNMT3A fusion proteins, blocking CTCF binding and interfering with DNA cycling, which changed the expression of genes in adjacent rings.”
Role of DNA Methylation in the Resistance to Therapy in Solid Tumors
Romero‐Garcia, S., Prado-Garcı́a, H., & Carlos‐Reyes, Á. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01152 · Cited by 176
“dCas9 can also be linked to DNMT3A or ten-eleven translocation-1 (TET1) enzymes, generating the systems dCas9-DNMT3A or dCas9TET1, respectively (218, 219).”
BackgroundThe importance of DNA methylation of exons on alternative splicing
Shayevitch, R., Askayo, D., Keydar, I., & Ast, G. (2018) · RNA · doi:10.1261/rna.064865.117 · Cited by 186
“…mainly to promoters and transcription start sites (van der Gun et al. 2010; Maeder et al. 2013; Siddique et al. 2013; Bernstein et al. 2015), whereas others use dCas9 as a platform to target the DNA (Choudhury et al. 2016; Liu et al. 2016; Morita et al. 2016; Xuet al. 2016;Okadaet al. 2017).”
BackgroundMethodInfluentialEpigenetics and Epigenomics: Implications for Diabetes and Obesity
Rosen, E. D., Kaestner, K. H., Natarajan, R. D., Patti, M., Sallari, R. C., Sander, M., & Suszták, K. (2018) · Diabetes · doi:10.2337/db18-0537 · Cited by 180
“Thus, the Jaenisch laboratory used a modified CRISPR/Cas9 system to either methylate or demethylate key regulatory gene elements on cytosine residues to control their expression (60).”
MethodGenome Editing—Principles and Applications for Functional Genomics Research and Crop Improvement
Zhang, H., Zhang, J., Lang, Z., Botella, J. R., & Zhu, J. (2017) · Critical Reviews in Plant Sciences · doi:10.1080/07352689.2017.1402989 · Cited by 179
“For example, in mammalian cells, CRISPR/dCas9 has been fused with DNA methyltransferase 3a (DNMT3a) and DNA demethylase (TET1) to induce DNA methylation or demethylation respectively in target regions (Liu et al., 2016).”
BackgroundWang, K., & Chang, H. Y. (2018) · Circulation Research · doi:10.1161/circresaha.118.310998 · Cited by 180
Liu, P., Chen, M., Liu, Y., Qi, L. S., & Ding, S. (2018) · Cell stem cell · doi:10.1016/j.stem.2017.12.001 · Cited by 170
Applications of CRISPR/Cas System to Bacterial Metabolic Engineering
Cho, S., Shin, J., & Cho, B. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041089 · Cited by 180
“This system has been intensively repurposed for genome engineering, metabolic engineering [20], epigenetic modification [21], functional genomics [11], genome imaging [22], and DNA/RNA chromatin immunoprecipitation [23].”
MethodOxidative stress-mediated beta cell death and dysfunction as a target for diabetes management
Dinić, S., Јovanović, J. A., Uskoković, A. S., Mihailović, M., Grdović, N., Tolić, A., Rajić, J., Đorđević, M., & Vidaković, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1006376 · Cited by 196
DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge
Castillo‐Aguilera, O., Depreux, P., Halby, L., Arimondo, P. B., & Goossens, L. (2017) · Biomolecules · doi:10.3390/biom7010003 · Cited by 166
“In addition, a clustered regularly interspaced palindromic repeat clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system was proven to affect the DNA methylation pattern, and it may represent a novel profitable approach [151].”
BackgroundChen, L., Lin, Y. T., Gallegos, D. A., Hazlett, M. F., Gómez-Schiavon, M., Yang, M. G., Kalmeta, B., Zhou, A. S., Holtzman, L., Gersbach, C. A., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.032 · Cited by 160
“As strategies emerge to allow the application of CRISPR to manipulate the chromatin state in vivo (Liu et al., 2016), these tools will present an opportunity to carry the findings revealed here to a circuit level of analysis.”
Genome-wide tracking of dCas9-methyltransferase footprints
Galonska, C., Charlton, J., Mattei, A. L., Donaghey, J., Clement, K., Gu, H., Mohammad, A. W., Stamenova, E. K., Cacchiarelli, D., Klages, S., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02708-5 · Cited by 160
Neuropathology of suicide: Recent findings and future directions
Lutz, P.-E., Mechawar, N., & Turecki, G. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.141 · Cited by 158
Xu, W., Xu, M., Wang, L., Zhou, W., Xiang, R., Shi, Y., Zhang, Y., & Piao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0081-6 · Cited by 170
In Situ Gene Therapy via AAV-CRISPR-Cas9-Mediated Targeted Gene Regulation
Moreno, A. M., Fu, X., Zhu, J., Katrekar, D., Shih, Y.-R. V., Marlett, J., Cabotaje, J., Tat, J., Naughton, J., Lisowski, L., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.04.017 · Cited by 159
Wang, X., Hu, L., Hao, J., Liao, L., Chiu, Y.-T., Shi, M., & Wang, Y. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0292-7 · Cited by 155
Rapid and reversible epigenome editing by endogenous chromatin regulators
Braun, S. M. G., Kirkland, J. G., Chory, E. J., Husmann, D., Calarco, J. P., & Crabtree, G. R. (2017) · Nature Communications · doi:10.1038/s41467-017-00644-y · Cited by 166
Losing DNA methylation at repetitive elements and breaking bad
Pappalardo, X. G., & Barra, V. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00400-z · Cited by 165
TALENs—an indispensable tool in the era of CRISPR: a mini review
Bhardwaj, A., & Nain, V. (2021) · Journal of Genetic Engineering and Biotechnology · doi:10.1186/s43141-021-00225-z · Cited by 162
“Mito-TALENs (mitochondrial-targeted TALENs) have also been proven to be effectively treating human mitochondrial disorders affected by mtDNA mutations, such as Leber’s hereditary optic neuropathy, ataxia, neurogenic muscle fatigue, and retinal pigmentosa [55].”
BackgroundVaz, R., Hofmeister, W., & Lindstrand, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061296 · Cited by 115
Lagger, S., Connelly, J. C., Schweikert, G., Webb, S., Selfridge, J., Ramsahoye, B. H., Yu, M., DeSousa, D., Seiser, C., He, C., et al. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006793 · Cited by 146
“In contrast to published reports [17,35], we found no evidence for MeCP2 binding to hmCG in native brain (S3G and S3H Fig).”
ResultA comprehensive epigenome atlas reveals DNA methylation regulating skeletal muscle development
Yang, Y., Fan, X., Yan, J., Chen, M., Zhu, M., Tang, Y., Liu, S., & Tang, Z. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1203 · Cited by 146
“Further investigation using new epigenetic editing tools for targeted DNA methylation will be required to elucidate the detailed mechanisms of dynamic DNA methylation during skeletal muscle development (77).”
Editing the Epigenome: Reshaping the Genomic Landscape
Holtzman, L., & Gersbach, C. A. (2018) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083117-021632 · Cited by 147
Genetic–epigenetic interactions in cis: a major focus in the post-GWAS era
Do, C., Shearer, A., Suzuki, M., Terry, M. B., Gelernter, J. E., Greally, J. M., & Tycko, B. (2017) · Genome biology · doi:10.1186/s13059-017-1250-y · Cited by 145
Stem Cells, Genome Editing, and the Path to Translational Medicine
Soldner, F., & Jaenisch, R. (2018) · Cell · doi:10.1016/j.cell.2018.09.010 · Cited by 144
“, 2014) or active domains of epigenetic modifiers such as DNA methylation/demethylation or histone acetylation can change the activity of non-coding regulatory elements (Amabile et al., 2016; Kearns et al., 2015; Liu et al., 2016).”
Self-citation
Metadata
- Authors
- Liu, X. S., Wu, H., Ji, X., Stelzer, Y., Wu, X., Czauderna, S., Shu, J., Dadon, D., Young, R. A., & Jaenisch, R.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Jagiellonian University (PL)
- Corresponding author
- Jaenisch, Rudolf
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 167
- Issue
- 1
- Pages
- 233-247.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5062609
- OpenAlex
- W2521981506
- Cited by
- 1,224
- References
- 58
- Citations by year
- 2026: 98 · 2025: 104 · 2024: 98 · 2023: 107 · 2022: 104 · 2021: 137 · 2020: 124 · 2019: 155 · 2018: 161 · 2017: 123 · 2016: 11
- FWCI
- 77.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Damon Runyon Cancer Research Foundation
- Helen Hay Whitney Foundation
- National Alliance for Research on Schizophrenia and Depression
- Narodowym Centrum Nauki
- National Institutes of Health
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (R37CA084198, P30CA014051)
- National Institute of General Medical Sciences (R01GM114864, T32GM007287)
- National Institute of Neurological Disorders and Stroke (R01NS088538)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD045022, R37HD045022)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- 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
- Keywords
- TET1, DNMT3A, dCas9, promoter activation, gene silencing, BDNF promoter, DNA looping, epigenetic regulation
- MeSH terms
- Gene Editing, CCCTC-Binding Factor, CRISPR-Associated Protein 9, DNA Methyltransferase 3A, Animals, Bacterial Proteins, Cell Line, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Endonucleases, Enhancer Elements, Genetic, Neurons, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Repressor Proteins, Genome, MyoD Protein, CpG Islands, DNA Methylation, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, Mice, Clustered Regularly Interspaced Short Palindromic Repeats
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