The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.
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]
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“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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Citations
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · cited 2×
“STAR+METHODS Detailed methods are provided in the online version of this paper and include the following: d KEY RESOURCES TABLE d CONTACT FOR REAGENT AND RESOURCE SHARING d EXPERIMENTAL MODEL AND SUBJECT DETAILS B Mouse lines and breeding strategies B Mouse primary cortical neuron culture, EDU labeling, and neural ind…”
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
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116 · cited 6×
“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
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339 · 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).”
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
Bird, A. (2002) · Genes & Development · doi:10.1101/gad.947102 · Cited by 7,124 · cited 2×
“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).”
Cited by
Sorted by citations
The diverse roles of DNA methylation in mammalian development and disease
Greenberg, M., & Bourc’his, D. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0159-6 · Cited by 2,272
The CRISPR tool kit for genome editing and beyond
Adli, M. (2018) · Nature Communications · doi:10.1038/s41467-018-04252-2 · Cited by 1,545
The DNA methyltransferase family: a versatile toolkit for epigenetic regulation
Lyko, F. (2017) · Nature Reviews Genetics · doi:10.1038/nrg.2017.80 · Cited by 1,510
Integrative single-cell analysis
Stuart, T., & Satija, R. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0093-7 · Cited by 1,460
Transcriptional Addiction in Cancer
Bradner, J. E., Hnisz, D., & Young, R. A. (2017) · Cell · doi:10.1016/j.cell.2016.12.013 · Cited by 1,229
“In glioma cells that harbor mutations in the IDH1 gene, hypermethylation of insulated neighborhood anchor sites occurs, which leads to loss of CTCF binding at those anchors and activation of oncogenes that were previously silent in the intact neighborhoods (Flavahan et al., 2016).”
InfluentialSelf-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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