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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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In the citing paper
“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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STAR: ultrafast universal RNA-seq aligner
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InfluentialModel-based Analysis of ChIP-Seq (MACS)
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“Peaks are called using MACS (Zhang et al., 2008) with default settings.”
Self-citationA Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
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“Clustered regularly interspaced palindromic repeats (CRISPR), a type II bacterial adaptive immune system, has been modified to target the Cas9 nuclease to the desired genomic loci with sequence-specific guide RNAs for genome editing (Cong et al., 2013; Jinek et al., 2012; Mali et al., 2013).”
InfluentialMultiplex Genome Engineering Using CRISPR/Cas Systems
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“Clustered regularly interspaced palindromic repeats (CRISPR), a type II bacterial adaptive immune system, has been modified to target the Cas9 nuclease to the desired genomic loci with sequence-specific guide RNAs for genome editing (Cong et al., 2013; Jinek et al., 2012; Mali et al., 2013).”
Self-citationRNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210 · cited 2×
“Clustered regularly interspaced palindromic repeats (CRISPR), a type II bacterial adaptive immune system, has been modified to target the Cas9 nuclease to the desired genomic loci with sequence-specific guide RNAs for genome editing (Cong et al., 2013; Jinek et al., 2012; Mali et al., 2013).”
DNA methylation patterns and epigenetic memory
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“Mammalian DNA methylation at 5-cytosine plays critical roles in many biological processes, including genomic imprinting, cell fate determination, chromatin architecture organization, and regulation of gene expression (Bird, 2002; Jaenisch and Bird, 2003; Smith and Meissner, 2013).”
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · cited 2×
“…are constrained within larger CTCF-mediated loops called insulated neighborhoods (Dowen et al., 2014; Ji et al., 2016; Phillips-Cremins et al., 2013), which, in turn, can form clusters of loops that contribute to topologically associating domains (TADs) (Dixon et al., 2012; Nora et al., 2012).”
Jaenisch, R., & Bird, A. (2003) · Nature Genetics · doi:10.1038/ng1089 · Cited by 6,325 · cited 3×
“Genetic studies have revealed that DNA methylation is essential for mammalian development and adaptation to environmental signals (Jaenisch and Bird, 2003).”
Self-citationRepurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression
Qi, L. S., Larson, M. H., Gilbert, L. A., Doudna, J. A., Weissman, J. S., Arkin, A. P., & Lim, W. A. (2013) · Cell · doi:10.1016/j.cell.2013.02.022 · Cited by 5,016 · cited 2×
“…activator/suppressor, chromatin modifier, and green fluorescence protein to regulate gene expression, to modify chromatin, and to image genomic loci respectively (Chen et al., 2013; Gilbert et al., 2013; Hilton et al., 2015; Jinek et al., 2012; Konermann et al., 2015; Qi et al., 2013).”
Human DNA methylomes at base resolution show widespread epigenomic differences
Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q.-M., et al. (2009) · Nature · doi:10.1038/nature08514 · Cited by 4,673 · cited 2×
“Owing to the advancement in sequencing technologies, single-nucleotide resolution methylation maps for many types of human and mouse cells and tissues have been depicted (Lister et al., 2009, 2013).”
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Maybe you can turn me on: CRISPRa-based strategies for therapeutic applications
Bećirović, E. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04175-8 · Cited by 52
“Among those, CRISPRa modules developed in the past contain Cas9 linked to demethylases such as dCas9 fused to the catalytic domain of ten-eleven translocation dioxygenase1 (TET1), [34], to catalytic histone acetyltransferase (HAT) core domain of the human E1Aassociated protein p300 [35], or to histone methyltransferas…”
BackgroundCRISPR activation screens: navigating technologies and applications
Clark, T., Waller, M. A., Loo, L., Moreno, C. L., Denes, C. E., & Neely, G. G. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.02.007 · Cited by 54
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“CRISPR-on and the similar CRISPR-mediated transcriptional inhibition [50] and CRISPR-mediated epigenetic modification [51] techniques, all requiring precise TSS knowledge, have the potential to revolutionize developmental studies in model systems not amenable to traditional genetics-based analysis.”
BackgroundCTCF maintains regulatory homeostasis of cancer pathways
Aitken, S. J., Ibarra-Soria, X., Kentepozidou, E., Flicek, P., Feig, C., Marioni, J. C., & Odom, D. T. (2018) · Genome biology · doi:10.1186/s13059-018-1484-3 · Cited by 47
“Complete removal of CTCF has catastrophic effects caused by massive dysregulation of the 3D genome [19, 22, 50, 51].”
BackgroundDNA Methylation Patterning and the Regulation of Beta Cell Homeostasis
Parveen, N., & Dhawan, S. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.651258 · Cited by 48
CRISPR–Cas-mediated transcriptional control and epi-mutagenesis
Gardiner, J., Ghoshal, B., Wang, M., & Jacobsen, S. E. (2022) · PLANT PHYSIOLOGY · doi:10.1093/plphys/kiac033 · Cited by 46
“…human TENELEVEN TRANSLOCATION1 (TET1) can also cause transcriptional activation (Maeder et al., 2013; Amabile et al., 2016; Choudhury et al., 2016; Liu et al., 2016; Morita et al., 2016; Xu et al., 2016; Lo et al., 2017; Okada et al., 2017; Gallego-Bartolom e et al., 2018; Li et al., 2020; Tang…”
Bidirectional epigenetic editing reveals hierarchies in gene regulation
Pacalin, N. M., Steinhart, Z., Shi, Q., Belk, J. A., Dorovskyi, D., Kraft, K., Parker, K. R., Shy, B. R., Marson, A., & Chang, H. Y. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02213-3 · Cited by 49
“We anticipate that future applications of CRISPRai can further extend its capabilities for studying non-coding elements by multiplexing more than two simultaneous perturbations or using additional epigenetic effector domains, such as DNA methyltransferase or demethylase 92 .”
Epigenetics and testicular germ cell tumors
Buljubašić, R., Buljubašić, M., Bojanac, A. K., Ulamec, M., Vlahović, M., Ježek, D., Bulić‐Jakuš, F., & Sinčić, N. (2018) · Gene · doi:10.1016/j.gene.2018.03.072 · Cited by 46
“, p53) that were impinged on by the favorable environment for the development of TGCTs may be proposed (Liu et al., 2016).”
BackgroundLau, C., Ho, J. W., Lo, P. K., & Tin, C. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.04.015 · Cited by 46
Amann, T., Schmieder, V., Faustrup Kildegaard, H., Borth, N., & Andersen, M. R. (2019) · Biotechnology and Bioengineering · doi:10.1002/bit.27101 · Cited by 46
“…enables for instance gene transcription activation or deactivation by demethylation or methylation of CpG islands within a promoter, or silencing by targeting transcription interfering proteins to a specific genome region (Liu et al., 2016; O’Geen et al., 2017; Xiong et al., 2019; Xu et al., 2016).”
Epigenetic insights into multiple sclerosis disease progression
Kular, L., & Jagodic, M. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13045 · Cited by 49
Comparative analysis of dCas9-VP64 variants and multiplexed guide RNAs mediating CRISPR activation
Omachi, K., & Miner, J. H. (2022) · PLoS ONE · doi:10.1371/journal.pone.0270008 · Cited by 48
“Based on a different concept regarding transcriptional inducers, dCas9 fused to epigenetic modifiers such as p300, histone acetylase [14] and Tet1, a CpG DNA demethylase [15], have also been used to activate endogenous genes.”
BackgroundDNA Methylation in Regulatory T Cell Differentiation and Function: Challenges and Opportunities
Bai, L., Hao, X., Keith, J., & Feng, Y. (2022) · Biomolecules · doi:10.3390/biom12091282 · Cited by 46
Improvements of TKC Technology Accelerate Isolation of Transgene-Free CRISPR/Cas9-Edited Rice Plants
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Hoffmann, M. D., Mathony, J., zu Belzen, J. U., Harteveld, Z., Aschenbrenner, S., Stengl, C., Grimm, D., Correia, B. E., Eils, R., & Niopek, D. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1198 · Cited by 45
“regulation of endogenous transcription (4,5), epigenetic reprogramming (6-8), DNA labeling (9,10) and base editing (11,12).”
BackgroundNanobody-mediated control of gene expression and epigenetic memory
Van, M. V., Fujimori, T., & Bintu, L. (2021) · Nature Communications · doi:10.1038/s41467-020-20757-1 · Cited by 44
Shareef, S. J., Bevill, S. M., Raman, A. T., Aryee, M. J., van Galen, P., Hovestadt, V., & Bernstein, B. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00910-x · Cited by 43
Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
McAllan, L., Baranas̆ić, D., Villicaña, S., Brown, S., Zhang, W., Lehne, B. C., Adamo, M., Jenkinson, A. D., Elkalaawy, M., Mohammadi, B., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38439-z · Cited by 48
Emerging mechanisms underlying astrogenesis in the developing mammalian brain
Takouda, J., Katada, S., & Nakashima, K. (2017) · Proceedings of the Japan Academy. Series B, Physical and biological sciences · doi:10.2183/pjab.93.024 · Cited by 39
Vogt, G. (2018) · Journal of Biosciences · doi:10.1007/s12038-018-9741-x · Cited by 44
“It is now well established that genes can be activated and silenced by demethylation and remethylation of promoters (Liu et al. 2016b).”
BackgroundRobinson, N. A., Johnsen, H., Moghadam, H. K., Andersen, Ø., & Tveiten, H. (2019) · G3 Genes Genomes Genetics · doi:10.1534/g3.119.400152 · Cited by 44
CpG traffic lights are markers of regulatory regions in human genome
Lioznova, A. V., Khamis, A. M., Artemov, A. V., Besedina, E. G., Ramensky, V. E., Bajić, V. B., Kulakovskiy, I. V., & Medvedeva, Y. A. (2019) · BMC Genomics · doi:10.1186/s12864-018-5387-1 · Cited by 45
An Improved CRISPR/dCas9 Interference Tool for Neuronal Gene Suppression
Duke, C. G., Bach, S. V., Revanna, J. S., Sultan, F. A., Southern, N. T., Davis, M. N., Carullo, N. V. N., Bauman, A. J., Phillips, R. A., & Day, J. J. (2020) · Frontiers in Genome Editing · doi:10.3389/fgeed.2020.00009 · Cited by 40
“Mutation of the catalytic domain of Cas9 to generate nuclease-dead Cas9 (dCas9) preserves its homing function and also enables a diverse array of applications (Liu et al., 2016; Savell and Day, 2017; Pickar-Oliver and Gersbach, 2019; Zhang, 2019).”
MethodDNA methylation signatures of autoimmune diseases in human B lymphocytes
Zouali, M. (2020) · Clinical Immunology · doi:10.1016/j.clim.2020.108622 · Cited by 45
Park, Y. J., Lee, S., Lim, S., Nahmgoong, H., Ji, Y., Huh, J. Y., Alfadda, A. A., Kim, S., & Kim, J. B. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021073118 · Cited by 44
“These changes in CTCF occupancy have been linked to pathogenicity by causing aberrant chromosome looping between distal cis-regulatory elements and their target promoters that promote altered gene expression (10, 12, 13).”
BackgroundPiferrer, F. (2021) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2020.0110 · Cited by 44
“To this end, help can come from manipulations of the epigenome by the use of DNA methyltransferase inhibitors such as 5-aza-20-deoxycytidine (5-aza-dC), shown to be able to alter sex ratios in zebrafish, Danio rerio [69], or the more recently developed technique to edit the methylome in the mammalian genome [70]; and…”
MethodThe Intrinsic and Extrinsic Effects of Tet Proteins During Gastrulation
Cheng, S., Mittnenzweig, M., Mayshar, Y., Lifshitz, A., Dunjić, M., Rais, Y., Ben-Yair, R., Gehrs, S., Chomsky, E., Mukamel, Z., et al. (2021) · Cell · doi:10.1016/j.cell.2022.06.049 · Cited by 43
Self-citationArgonaute 4 as an Effector Protein in RNA-Directed DNA Methylation in Human Cells
Chalertpet, K., Pin-on, P., Aporntewan, C., Patchsung, M., Ingrungruanglert, P., Israsena, N., & Mutirangura, A. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00645 · Cited by 43
“The ΔΔCT method (Livak and Schmittgen, 2001) was used to calculate the amount of AGO4-bound LINE-1 or Alu in AGO4 plasmid overexpressing cells compared with pcDNA3.”
MethodCRISPR/Cas9: Regulations and challenges for law enforcement to combat its dual-use
Mir, T. U. G., Wani, A. K., Akhtar, N., & Shukla, S. (2022) · Forensic Science International · doi:10.1016/j.forsciint.2022.111274 · Cited by 50
CRISPR-Cas System: The Current and Emerging Translational Landscape
Bhokisham, N., Laudermilch, E., Traeger, L. L., Bonilla, T. D., Ruíz-Estévez, M., & Becker, J. R. (2023) · Cells · doi:10.3390/cells12081103 · Cited by 46
Exploiting Single-Cell Tools in Gene and Cell Therapy
Bode, D., Cull, A. H., Rubio-Lara, J. A., & Kent, D. G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.702636 · Cited by 44
Kawamura, Y., Takouda, J., Yoshimoto, K., & Nakashima, K. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-017-9420-y · Cited by 42
“The fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables us to perform targeted negative and positive DNAmethylation editing, respectively (Liu et al. 2016, Morita et al. 2016).”
MethodPersonalised genome editing – The future for corneal dystrophies
Moore, T., Christie, K. A., Marshall, J., & Nesbit, M. A. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.01.004 · Cited by 44
Impact of Epigenetic Regulation on Head and Neck Squamous Cell Carcinoma
Bais, M. V. (2019) · Journal of Dental Research · doi:10.1177/0022034518816947 · Cited by 44
DNA methylation analysis and editing in single mammalian oocytes
Wei, Y., Lang, J., Zhang, Q., Yang, C., Zhao, Z., Zhang, Y., Du, Y., & Sun, Y. W. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817703116 · Cited by 41
Epigenetics and Type 2 Diabetes Risk
Dhawan, S., & Natarajan, R. D. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1168-8 · Cited by 46
Epigenetic dynamics in cancer stem cell dormancy
Ferrer, A. I., Trinidad, J. R., Sandiford, O. A., Etchegaray, J., & Rameshwar, P. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09882-x · Cited by 44
Epigenetics and individuality: from concepts to causality across timescales
Webster, A. K., & Phillips, P. C. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-024-00804-z · Cited by 48
“Despite this difficulty, proof-of-concept studies using dCas9 in several model organisms have been performed, including altering DNA methylation in mice 148 and H3K27me3 in killifish 149 .”
CRISPR RNA-guided autonomous delivery of Cas9
Wilkinson, R. A., Martin, C. D., Nemudryi, A. A., & Wiedenheft, B. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0173-y · Cited by 43
Recent Advances in Genome-Engineering Strategies
Boti, M. A., Athanasopoulou, K., Adamopoulos, P. G., Sideris, D. C., & Scorilas, A. (2023) · Genes · doi:10.3390/genes14010129 · Cited by 44
LATS kinase–mediated CTCF phosphorylation and selective loss of genomic binding
Luo, H., Yu, Q., Liu, Y., Tang, M., Liang, M., Zhang, D., Xiao, T. S., Wu, L., Tan, M., Ruan, Y., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaw4651 · Cited by 39
Soto, E. J. L., & Lipscombe, D. (2020) · eLife · doi:10.7554/elife.54879 · Cited by 40
“(Liu et al., 2016; Liu et al., 2018; Marina et al., 2016) and, as we show for dCAS9-TET1 targeted to”
BackgroundMethodResultInfluentialKlotho and the Treatment of Human Malignancies
Sachdeva, A., Gouge, J., Kontovounisios, C., Nikolaou, S., Ashworth, A., Lim, K. J., & Chong, I. Y.-S. (2020) · Cancers · doi:10.3390/cancers12061665 · Cited by 41
Wide Horizons of CRISPR-Cas-Derived Technologies for Basic Biology, Agriculture, and Medicine
Molla, K. A., Karmakar, S., & Islam, T. (2020) · Springer protocols handbooks/Springer protocols · doi:10.1007/978-1-0716-0616-2_1 · Cited by 42
Liao, Y., Huang, J., Liu, P., Zhang, C., Liu, J., Xia, M., Shang, C., Ooi, S., Chen, Y., Qin, S., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02202-3 · Cited by 40
Paving the way towards precise and safe CRISPR genome editing
Śledziński, P., Dabrowska, M., Nowaczyk, M., & Olejniczak, M. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107737 · Cited by 43
The Design and Application of DNA-Editing Enzymes as Base Editors
Rallapalli, K. L., & Komor, A. C. (2023) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052521-013938 · Cited by 44
Rajanathadurai, J., Perumal, E., & Sindya, J. (2024) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01455-3 · Cited by 40
“Furthermore, Liu et al. (2016) discovered that circulating miR-375 is a promising biomarker for prognosis and early detection in pancreatic cancer (He et al. 2024).”
CRISPR/Cas Derivatives as Novel Gene Modulating Tools: Possibilities and In Vivo Applications
Xu, X., Hulshoff, M. S., Tan, X., Zeisberg, M., & Zeisberg, E. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093038 · Cited by 41
“dCas9-TET1 is also used in another study to facilitate demethylation in vivo in the brain and skin of mice via lentiviral vectors [79].”
MethodPadayachee, J., & Singh, M. (2020) · Nanobiomedicine · doi:10.1177/1849543520983196 · Cited by 39
“These enzymes convert 50-mC to 5-hydroxymethylcytosine (5-hmc), which is corrected to C during DNA replication, removing methylation.(48,49) dCas9-TET fusions have been used to demethylate the BRCA1 gene in vitro in MCF-7 and HeLa cells, upregulating BRCA1 expression and enhancing the cytotoxic effect of the chemother…”
Kusumanchi, P., Liang, T., Zhang, T., Ross, R. A., Han, S., Chandler, K., Oshodi, A., Jiang, Y., Dent, A. L., Skill, N. J., et al. (2021) · Hepatology · doi:10.1002/hep.31800 · Cited by 39
“5F).(26) We designed two gRNA plasmids as described in the Materials and Methods section and cotransfected these plasmids with fused catalytically inactive mutant Cas9 (dCas9)DNMT3A or dCas9TET (Fig 5G).”
MethodRittiner, J. E., Cumaran, M., Malhotra, S., & Kantor, B. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.1035543 · Cited by 42
Myoediting: Toward Prevention of Muscular Dystrophy by Therapeutic Genome Editing
Zhang, Y., Long, C., Bassel‐Duby, R., & Olson, E. N. (2018) · Physiological Reviews · doi:10.1152/physrev.00046.2017 · Cited by 42
“ity and can be fused with different effectors, including cytidine deaminase, transcriptional activators/repressors, and epigenetic modifiers for different purposes, such as nucleotide conversion as well as genome and epigenome regulation (66, 126, 142, 179, 194, 196, 228, 274, 294).”
BackgroundKantor, B., O’Donovan, B., Rittiner, J. E., Hodgson, D., Lindner, N., Guerrero, S., Dong, W., Zhang, A., & Chiba‐Falek, O. (2024) · Nature Communications · doi:10.1038/s41467-024-50515-6 · Cited by 48
Yamazaki, T., Hatano, Y., Handa, T., Kato, S., Hoida, K., Yamamura, R., Fukuyama, T., Uematsu, T., Kobayashi, N., Kimurâ, H., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177764 · Cited by 38
Gödecke, N., Zha, L., Spencer, S., Behme, S., Riemer, P., Rehli, M., Häuser, H., & Wirth, D. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx601 · Cited by 39
“Multiplexing is usually required to achieve robust demethylation (65).”
Musunuru, K. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.10.002 · Cited by 38
Targeted in vivo epigenome editing of H3K27me3
Fukushima, H. S., Takeda, H., & Nakamura, R. (2019) · Epigenetics & Chromatin · doi:10.1186/s13072-019-0263-z · Cited by 37
“In vivo dCas9-based epigenome editing applications have been used for site-specific deubiquitylation by injection in nuclear transferred Xenopus oocyte [25] and targeted manipulation of DNA methylation in mouse oocyte by injection [26] and in mouse brain by in vivo electrophoresis [22, 23].”
MethodHan, F., JIANG, X. H., Li, Z., Zhuang, X., Zhang, X., Ouyang, W., Liu, W., Mao, C., Chen, Q., Huang, C., et al. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.10.038 · Cited by 38
Parker, E. L., Hofer, I. M. J., Rice, S. J., Earl, L., Anjum, S. A., Deehan, D. J., & Loughlin, J. A. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41473 · Cited by 38
“The PiggyBac 138-dCas9-TET1 vector (19) and modified 137transposase “helper” vector (20) were kind gifts from the laboratory of R.”
MethodWang, S.-D., Wang, X., Zhao, Y. F., Xue, B.-H., Wang, X.-T., Chen, Y., Zhang, Z., Tian, Y.-R., Xie, F., & Qian, L. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00852-7 · Cited by 37
“TET1 is an enzyme that acts in the mammalian brain; it is involved in the regulation of cognitive functions and exerts 5mC demethylation [73, 74].”
BackgroundSweat gland regeneration: Current strategies and future opportunities
Chen, R., Zhu, Z., Ji, S., Geng, Z., Hou, Q., Sun, X., & Fu, X. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120201 · Cited by 38
Understanding and Engineering Chromatin as a Dynamical System across Length and Timescales
Johnstone, C. P., Wang, N., Sevier, S. A., & Galloway, K. E. (2020) · Cell Systems · doi:10.1016/j.cels.2020.09.011 · Cited by 36
Danoff, J. S., Connelly, J. J., Morris, J. P., & Perkeybile, A. M. (2021) · Comprehensive Psychoneuroendocrinology · doi:10.1016/j.cpnec.2021.100098 · Cited by 37
“However, using CRISPRCas9 systems which allow for target specificity, it is now possible to change DNA methylation at a specific gene locus by coupling a deactivated Cas9 (which prevents cutting of the DNA) conjugated to epigenetic enzymes like DNMT3a (which methylates cytosines) or Tet1 (which initiates demethylation…”
MethodThe Epigenetics of Early Life Adversity: Current Limitations and Possible Solutions
Barnett-Burns, S., Almeida, D. M., & Turecki, G. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2018.01.008 · Cited by 35
Epigenetic Regulation Of Axon Regeneration and Glial Activation in Injury Responses
Wahane, S., Halawani, D., Zhou, X., & Zou, H. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00640 · Cited by 36
Neuronal and glial DNA methylation and gene expression changes in early epileptogenesis
Berger, T. C., Vigeland, M. D., Hjorthaug, H. S., Etholm, L., Nome, C. G., Taubøll, E., Heuser, K., & Selmer, K. K. (2019) · PLoS ONE · doi:10.1371/journal.pone.0226575 · Cited by 36
Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing
Hanzawa, N., Hashimoto, K., Yuan, X., Kawahori, K., Tsujimoto, K., Hamaguchi, M., Tanaka, T., Nagaoka, Y., Nishina, H., Morita, S., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-62035-6 · Cited by 35
CRISPR-assisted transcription activation by phase-separation proteins
Liu, J., Chen, Y., Nong, B., Luo, X., Cui, K., Li, Z., Zhang, P., Tan, W., Yang, Y., Ma, W., et al. (2023) · Protein & Cell · doi:10.1093/procel/pwad013 · Cited by 37
“…activators, where nuclease-dead Cas proteins are fused to transcription factors (TFs) (e.g., VP64) (Maeder et al., 2013; Perez-Pinera et al., 2013; Chavez et al., 2015) or DNA/histone modification enzymes (e.g., TET1 or the catalytic core domain of p300) (Hilton et al., 2015; Liu et al., 2016).”
BackgroundA modular dCas9-based recruitment platform for combinatorial epigenome editing
Swain, T., Pflueger, C., Freytag, S., Poppe, D., Pflueger, J., Nguyen, T. V., Li, J. K., & Lister, R. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad1108 · Cited by 42
Gene regulation technologies for gene and cell therapy
Butterfield, G. L., Reisman, S. J., Iglesias, N., & Gersbach, C. A. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.004 · Cited by 43
Role of DNA De Novo (De)Methylation in the Kidney in Salt-Induced Hypertension
Liu, P., Liu, Y., Liu, H., Pan, X., Li, Y., Usa, K., Mishra, M. K., Nie, J., & Liang, M. (2018) · Hypertension · doi:10.1161/hypertensionaha.118.11650 · Cited by 35
The role of DNA methylation and hydroxymethylation in immunosenescence
Johnson, N. D., & Conneely, K. N. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.01.011 · Cited by 35
From fiction to science: clinical potentials and regulatory considerations of gene editing
Schacker, M., & Seimetz, D. (2019) · Clinical and Translational Medicine · doi:10.1186/s40169-019-0244-7 · Cited by 36
“[82] have demonstrated that fusing the de novo DNA methyltransferase 3a (Dnmt3a) or the methylcytosine dioxygenase Tet1 to dCas9 enables targeted methylation or demethylation and subsequent functional repression or activation of genes, respectively.”
BackgroundTargeting Epigenetic Modifications in Uveal Melanoma
Baradaran, P. C., Kozovská, Z., Furdová, A., & Smolková, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155314 · Cited by 36
Minárovits, J. (2020) · Anaerobe · doi:10.1016/j.anaerobe.2020.102300 · Cited by 35
Delivery Platforms for CRISPR/Cas9 Genome Editing of Glial Cells in the Central Nervous System
Meneghini, V., Peviani, M., Luciani, M., Zambonini, G., & Gritti, A. (2021) · Frontiers in Genome Editing · doi:10.3389/fgeed.2021.644319 · Cited by 36
“The combination of DNA methylation with H3K9me3 modification improved the stability of FMR1 activation for up to 4 weeks in FXR hiPSCs, although it is not clear if it is reproducible in more committed cells (Liu et al., 2016).”
BackgroundSelective Xi reactivation and alternative methods to restore MECP2 function in Rett syndrome
Grimm, N.-B., & Lee, J. T. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.01.007 · Cited by 34
Tutorial: design and execution of CRISPR in vivo screens
Braun, C. J., Adames, A. C., Saur, D., & Rad, R. (2022) · Nature Protocols · doi:10.1038/s41596-022-00700-y · Cited by 38
Liu, M.-Y., Wei, L., Zhu, X., Ding, H.-C., Li, H., Li, H., Li, Y.-Y., Zhou, H., Li, L.-D., Du, Z.-W., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01898-9 · Cited by 38
Self-citationDNA Methylation Dynamics in Response to Drought Stress in Crops
Rao, X., Yang, S., Lü, S., & Yang, P. (2024) · Plants · doi:10.3390/plants13141977 · Cited by 37
“…editing technologies have been successfully applied for precise chromatin perturbations [111–113]. regulate the methylation status at the promoter region of a targeted For example, the fusion protein of Tet1 or Dnmt3a with a catalytically inactive dCas9 has been shown to reporter gene [112”
Applications of the CRISPR/Cas system beyond gene editing
Anton, T., Karg, E., & Bultmann, S. (2018) · Biology Methods and Protocols · doi:10.1093/biomethods/bpy002 · Cited by 32
Genome Editing for CNS Disorders
Duarte, F. T., & Déglon, N. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.579062 · Cited by 36
Maternal obesity as a risk factor for developing diabetes in offspring: An epigenetic point of view
Lecoutre, S., Maqdasy, S., & Breton, C. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i4.366 · Cited by 35
Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization
Scelfo, A., Barra, V., Abdennur, N. A., Spracklin, G., Busato, F., Salinas‐Luypaert, C., Bonaiti, E., Velasco, G., Bonhomme, F., Chipont, A., et al. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202307026 · Cited by 35
“Alternative strategies achieved targeted demethylation using a fusion of the TET enzyme and inactive Cas9 (dCas9) (Choudhury et al., 2016; Liu et al., 2016) or exploiting the steric hindrance created by dCas9 on the DNA preventing DNMT binding (Sapozhnikov and Szyf, 2021).”
MethodEngineering CRISPR mouse models of cancer
Weber, J., & Rad, R. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.04.001 · Cited by 33
Origins of DNA methylation defects in Wilms tumors
Anvar, Z., Acurzio, B., Roma, J. M., Cerrato, F., & Verde, G. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.013 · Cited by 32
Applications of CRISPR/Cas9 in the Mammalian Central Nervous System.
Savell, K. E., & Day, J. J. (2017) · PubMed · Cited by 33
The 3D Genome as a Target for Anticancer Therapy
Kantidze, O. L., Gurova, K. V., Studitsky, V. M., & Razin, S. V. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.09.011 · Cited by 36
“sites have been reported [84], small molecule compounds specifically inhibiting DNA-binding or dimerization (oligomerization) activities of CTCF have yet to be discovered.”
BackgroundCRISPR Interference–Potential Application in Retinal Disease
Peddle, C. F., Fry, L. E., McClements, M. E., & MacLaren, R. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072329 · Cited by 33
“dCas9 has been successfully fused to proteins which alter the chemical tags on histone molecules: fusion to methyltransferase domains inactivates genes, and fusion to proteins, which remove methyl groups, activates repressed genes [29,30].”
BackgroundInterrogation of the dynamic properties of higher-order heterochromatin using CRISPR-dCas9
Gao, Y., Han, M., Shang, S., Wang, H., & Qi, L. S. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.07.034 · Cited by 33
Vinel, C., Rosser, G., Guglielmi, L., Constantinou, M., Pomella, N., Zhang, X., Boot, J. R., Jones, T. A., Millner, T. O., Dumas, A. A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26297-6 · Cited by 33
Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat
Li, F., Jia, J., Movahed, M., Cui, X., Cao, Q., Wu, R., Chen, Z., Yu, L., Pan, Y., Shi, H., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27141-7 · Cited by 34
“demethylation, tet methylcytosine dioxygenase 1 (TET1) (dCas9-TET1CD) (Amabile et al., 2016; Liu et al., 2016; Morita et al., 2016; Vojta et al., 2016; Xu et al., 2016) (Suppl.”
BackgroundMethodInfluentialLi, J., Pinto‐Duarte, A., Zander, M., Cuoco, M. S., Lai, C.-Y., Osteen, J. K., Fang, L., Luo, C., Lucero, J. D., Castanon, R., et al. (2022) · eLife · doi:10.7554/elife.66909 · Cited by 40
“Future work focusing on earlier developmental stages, and using targeted methods to manipulate epigenetic marks in local genomic regions (Liu et al., 2016), may help elucidate the causal interactions among epigenetic modifications that are critical for neuronal maturation and function.”
Mammalian DNA methylome dynamics: mechanisms, functions and new frontiers
Wei, A., & Wu, H. (2022) · Development · doi:10.1242/dev.182683 · Cited by 34
Self-citationApplications of Alternative Nucleases in the Age of CRISPR/Cas9
Guha, T. K., & Edgell, D. R. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122565 · Cited by 37
Reversing the Central Dogma: RNA-guided control of DNA in epigenetics and genome editing
Chang, H. Y., & Qi, L. S. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.01.010 · Cited by 33
Clinical translation of human iPSC technologies: advances, safety concerns, and future directions
Dhaiban, S., Chandran, S., Noshi, M., & Sajini, A. A. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1627149 · Cited by 39
“…screening and single-cell RNA sequencing to identify blocks in reprogramming and adjust experimental conditions CRISPR/Cas9 has been used to modify epigenetic regulators and increase consistency in reprogrammed cell populations (Kearns et al., 2015; Liu et al., 2016; Meng et al., 2020).”
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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