Genomic discovery of potent chromatin insulators for human gene therapy
Abstract
Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator sequences that block transcriptional enhancers could mitigate or eliminate these risks, so far no human insulators with high functional potency have been identified. Here we describe a genomic approach for the identification of compact sequence elements that function as insulators. These elements are highly occupied by the insulator protein CTCF, are DNase I hypersensitive and represent only a small minority of the CTCF recognition sequences in the human genome. We show that the elements identified acted as potent enhancer blockers and substantially decreased the risk of tumor formation in a cancer-prone animal model. The elements are small, can be efficiently accommodated by viral vectors and have no detrimental effects on viral titers. The insulators we describe here are expected to increase the safety of gene therapy for genetic diseases.
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Only a minority of CTCF sites function as insulators.
“Insulators are bound by the transcription factor CTCF (Bell et al., 1999), but only a minority of CTCF sites function as insulators (Liu et al., 2015).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Liu et al., 2015
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Park, J., Lim, J. M., Jung, I., Heo, S., Park, J., Chang, Y. J., Kim, H. K., Jung, D., Yu, J. H., Min, S., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.014 · Cited by 39 · see citing works
Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses
Munshi, S., Neupane, K., Ileperuma, S. M., Halma, M. T. J., Kelly, J. A., Halpern, C. F., Dinman, J. D., Loerch, S., & Woodside, M. T. (2022) · Viruses · doi:10.3390/v14020177 · Cited by 38 · see citing works
“(3) Construction of bi-fluorescent reporter for cell-based assays: The reporter plasmid pJD2261 was constructed by cloning a gBlock (Integrated DNA Technologies, Coralville, IA, USA) encoding AcGFP, the HIV-1 −1 PRF signal, mCherry, and insulator A2 described previously [63] into PstI-digested pUC19 (Genbank accession…”
MethodGene therapy and genome editing for primary immunodeficiency diseases
Zhang, Z., Thrasher, A. J., & Zhang, F. (2019) · Genes & Diseases · doi:10.1016/j.gendis.2019.07.007 · Cited by 37 · see citing works
Pugacheva, E. M., Teplyakov, E., Wu, Q., Li, J., Chen, C., Meng, C., Liu, J., Robinson, S. M., Loukinov, D., Boukaba, A., et al. (2016) · Epigenetics & Chromatin · doi:10.1186/s13072-016-0084-2 · Cited by 35 · see citing works
“In addition to serving as a bona fide transcription factor, CTCF reads the epigenetic marks [33–36] and plays a key role in the formation of topologically associated domains (TADs) in chromatin [37–39], in remodeling chromatin structure [40], and in the formation of chromatin boundaries [29, 41].”
BackgroundFunctional Validation of a Constitutive Autonomous Silencer Element
Qi, H., Liu, M., Emery, D. W., & Stamatoyannopoulos, G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124588 · Cited by 31 · see citing works
“In addition, we required that these motifs belong to classes with over 50% probability of being occupied by CTCF as determined by ChIP-seq as previously described [4].”
BackgroundMethodInfluentialRegulation and Dysregulation of Chromosome Structure in Cancer
Hnisz, D., Schuijers, J., Li, C. H., & Young, R. A. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030617-050134 · Cited by 31 · see citing works
Novel extragenic genomic safe harbors for precise therapeutic T cell engineering
Odak, A., Yuan, H., Feucht, J., Cantu, A., Mansilla‐Soto, J., Kogel, F., Eyquem, J., Everett, J. K., Bushman, F. D., Leslie, C. S., et al. (2023) · Blood · doi:10.1182/blood.2022018924 · Cited by 29 · see citing works
Bell, C. C., Balic, J. J., Talarmain, L., Gillespie, A., Scolamiero, L., Lam, E. Y. N., Ang, C.-S., Faulkner, G. J., Gilan, O., & Dawson, M. A. (2024) · Nature Genetics · doi:10.1038/s41588-024-01749-z · Cited by 30 · see citing works
Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders
Cavalieri, V., Baiamonte, E., & Iacono, M. L. (2018) · Viruses · doi:10.3390/v10060316 · Cited by 28 · see citing works
Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine
Lange, M., Begolli, R., & Giakountis, A. (2021) · Non-Coding RNA · doi:10.3390/ncrna7030047 · Cited by 26 · see citing works
Mechanisms and Delivery of tRNA Therapeutics
Ward, C., Beharry, A., Tennakoon, R., Rozik, P., Wilhelm, S. D. P., Heinemann, I. U., & O’Donoghue, P. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00142 · Cited by 26 · see citing works
Choice of binding sites for CTCFL compared to CTCF is driven by chromatin and by sequence preference
Bergmaier, P., Weth, O., Dienstbach, S., Boettger, T., Galjart, N., Mernberger, M., Bartkuhn, M., & Renkawitz, R. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky483 · Cited by 25 · see citing works
“In this study, ENCODE datasets were used in order to determine the top 1000 unique 14 bp core sequences bound in each case by CTCF in at least 50 instances in the genome of K562 cells (31).”
MethodLee, H., Willi, M., Wang, C., Yang, C. M., Smith, H. E., Liu, C., & Hennighausen, L. G. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx185 · Cited by 25 · see citing works
“Our study also support findings from tissue culture cells and ESCs that only a minority of CTCF sites play a role as insulators (51) and ablation of several CTCF sites linked to insulated neighborhoods might be required to obtain changes in gene expression (14).”
ResultGoodman, M., Arumugam, P. I., Pillis, D. M., Loberg, A., Nasimuzzaman, M., Lynn, D., van der Loo, J. C. M., Dexheimer, P. J., Keddache, M. A., Bauer, T. R., et al. (2017) · Journal of Virology · doi:10.1128/jvi.01639-17 · Cited by 24 · see citing works
“Recently, CTCF binding sites experimentally inserted into the LV or FV LTR have been shown to reduce genotoxicity (35, 46, 47).”
BackgroundDNA repair and anti-cancer mechanisms in the long-lived bowhead whalePreprint
Firsanov, D., Zacher, M., Tian, X., Sformo, T. L., Zhao, Y., Tombline, G., Lu, J. Y., Zheng, Z., Perelli, L., Gurreri, E., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.07.539748 · Cited by 26 · see citing works
Self-assembled PEI nanomicelles with a fluorinated core for improved siRNA delivery
Chen, G., Xu, Y., Wu, P., & Wang, K. (2019) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2019.101403 · Cited by 22 · see citing works
Nanobody-based sandwich reporter system for living cell sensing influenza A virus infection
Cao, J., Zhong, N., Wang, G., Wang, M., Zhang, B., Fu, B., Wang, Y., Zhang, T., Zhang, Y., Yang, K., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-52258-7 · Cited by 19 · see citing works
Retroviral vector interactions with hematopoietic cells
Everson, E. M., & Trobridge, G. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.07.010 · Cited by 17 · see citing works
Insulators to Improve the Safety of Retroviral Vectors for HIV Gene Therapy
Browning, D. L., & Trobridge, G. D. (2016) · Biomedicines · doi:10.3390/biomedicines4010004 · Cited by 17 · see citing works
“New designs of synthetic insulators should incorporate the more recently described CTCF insulators from the human genome to potentially avoid insulator failure due to recombination [44].”
BackgroundShort tandem repeats are important contributors to silencer elements in T cells
Hussain, S., Sadouni, N., van Essen, D., Dao, L. T. M., Ferré, Q., Charbonnier, G., Torres, M., Gallardo, F., Lecellier, C., Sexton, T., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad187 · Cited by 16 · see citing works
“This is, however, consistent with a previous study that showed that the T39 region bound by CTCF functions as a strong silencer, but is devoid of insulator activity, thus suggesting that in some cases CTCF might be specifically required for silencer activity (32,87).”
BackgroundResultZimak, J., Wagoner, Z. W., Nelson, N. E., Waechtler, B. E., Schlosser, H., Kopecky, M., Wu, J., & Zhao, W. (2021) · Scientific Reports · doi:10.1038/s41598-021-81975-1 · Cited by 15 · see citing works
Controlling gene activation by enhancers through a drug-inducible topological insulator
Tsujimura, T., Takase, O., Yoshikawa, M., Sano, E., Hayashi, M., Hoshi, K., Takato, T., Toyoda, A., Okano, H., & Hishikawa, K. (2020) · eLife · doi:10.7554/elife.47980 · Cited by 16 · see citing works
“Blocking of enhancer activity by heterologously inserted CTCF-binding sites is consistent with previous studies (Bell et al., 1999; Hou et al., 2008; Liu et al., 2015).”
ResultGenomic context sensitivity of insulator functionPreprint
Ribeiro-dos-Santos, A. M., Hogan, M. S., Luther, R. D., Brosh, R., & Maurano, M. T. (2022) · Genome Research · doi:10.1101/gr.276449.121 · Cited by 14 · see citing works
“used to counter genotoxicity from transgene enhancer activation of endogenous oncogenes (Li et al. 2009; Liu et al. 2015).”
BackgroundMethodInfluentialDual AAV vectors for efficient delivery of large transgenes
Mittas, D. M., Riedmayr, L. M., Gavrilov, Z., Weber, V. J., Otify, D. Y., Mehlfeld, V., Szalontai, B., Ucambarlic, E., Gandor, C. L. A., Heigl, T., et al. (2025) · Nature Protocols · doi:10.1038/s41596-025-01243-8 · Cited by 16 · see citing works
Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells
Nishimura, T., Xu, H., 岩崎, 正., Karigane, D., Saavedra, B., Takahashi, Y., Suchy, F. P., Monobe, S., Martin, R. M., Ohtaka, M., et al. (2020) · Gene Therapy · doi:10.1038/s41434-020-0179-z · Cited by 14 · see citing works
Lemmens, M., Dorsheimer, L., Zeller, A., & Dietz, Y. (2024) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2024.503767 · Cited by 13 · see citing works
Browning, D., Collins, C., Hocum, J. D., Leap, D. J., Rae, D. T., & Trobridge, G. (2016) · Human Gene Therapy · doi:10.1089/hum.2015.110 · Cited by 15 · see citing works
Evidence for the in vivo safety of insulated foamy viral vectors
Browning, D. L., Everson, E. M., Leap, D. J., Hocum, J. D., Wang, H., Stamatoyannopoulos, G., & Trobridge, G. D. (2016) · Gene Therapy · doi:10.1038/gt.2016.88 · Cited by 13 · see citing works
Huang, H., Zhu, Q.-S., Jussila, A. P., Han, Y., Bintu, B., Kern, C., Conte, M., Zhang, Y.-X., Bianco, S., Chiariello, A., et al. (2020) · bioRxiv · doi:10.1101/2020.07.07.192526 · Cited by 14 · see citing works
“[0 - 62] [0 - 184] CTCF”
Ultrasound image-guided cancer gene therapy using iRGD dual-targeted magnetic cationic microbubbles
Zhu, Y., Arkin, G., Zeng, W., Huang, Y., Su, L., Guo, F., Ye, J., Wen, G., Xu, J., & Liu, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116221 · Cited by 12 · see citing works
Massively parallel characterization of insulator activity across the genome
Hong, C. K., Wu, Y., Erickson, A., Li, J., Federico, A. J., & Cohen, B. A. (2024) · Nature Communications · doi:10.1038/s41467-024-52599-6 · Cited by 12 · see citing works
“Neither cHS4 nor A2 show enhancer activity in plasmidreporter assays 15,16 (Fig.”
BackgroundInfluentialRapid and quantitative functional interrogation of human enhancer variant activity in live mice
Hollingsworth, E. W., Liu, T. A., Alcantara, J. A., Chen, C. X., Jacinto, S. H., & Kvon, E. Z. (2025) · Nature Communications · doi:10.1038/s41467-024-55500-7 · Cited by 11 · see citing works
“We thought to create a stronger syntheticinsulator (SI) consisting of A2 (two copies), ALOXE3, and 5 ’ -HS4 (two copies) insulators and placed it between two transgenes as well as in the vector backbone to prevent cross-activation between transgene copies 57,60,61 ( “ Methods ” ).”
InfluentialProspects of Non-Coding Elements in Genomic DNA Based Gene Therapy
Simna, S. P., & Han, Z. (2021) · Current Gene Therapy · doi:10.2174/1566523221666210419090357 · Cited by 11 · see citing works
Alexander Joel Federation, Polaski, D. R., Ott, C. J., Fan, A. H. S., Lin, C. Y., & Bradner, J. E. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/345413 · Cited by 11 · see citing works
“Moreover, in addition to active enhancers, accessibility measurements identify insulator CTCF loci and poised regulatory elements [15,16], confounding TRN models of active, steady-state transcription.”
BackgroundThe characteristics of CTCF binding sequences contribute to enhancer blocking activity
Tsang, F. H., Stolper, R. J., Hanifi, M., Cornell, L., Francis, H. S., Davies, B., Higgs, D. R., & Kassouf, M. T. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae666 · Cited by 10 · see citing works
Engineering Globin Gene Expression
Davis, R., Gurumurthy, A., Hossain, M. A., Gunn, E. M., & Bungert, J. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.12.004 · Cited by 10 · see citing works
“Current research focuses on identifying insulator elements that function like cHS4 but do not affect production of the therapeutic virus particles.(35)”
BackgroundRational design and construction of multi-copy biomanufacturing islands in mammalian cells
Altamura, R., Doshi, J., & Benenson, Y. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1214 · Cited by 11 · see citing works
“Finally, the collection of regulatory sequences was expanded with the addition of a list of published mammalian insulators: these are compact, 200–300 bp genetic elements that are bound by the CTCF transcription factor and have been shown to act as enhancer blockers (52).”
DNA writing at a single genomic site enables lineage tracing and analog recording in mammalian cellsPreprint
Loveless, T. B., Grotts, J. H., Schechter, M. W., Forouzmand, E., Carlson, C. K., Agahi, B. S., Liang, G., Ficht, M., Liu, B., Xie, X. S., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/639120 · Cited by 9 · see citing works
Retroviral Vector Technology for Gene Therapy: History, Current Landscape, and Future Prospects
Jaballah, S. A., Ali, L. M., Jehad, M. A., Akhlaq, S., Rizvi, T. A., & Mustafa, F. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169473 · Cited by 10 · see citing works
SHIELD: a platform for high-throughput screening of barrier-type DNA elements in human cells
Zhang, M., Ehmann, M. E., Matukumalli, S., Boob, A. G., Gilbert, D. M., & Zhao, H. (2023) · Nature Communications · doi:10.1038/s41467-023-41468-3 · Cited by 9 · see citing works
Safety and Efficacy of Retroviral and Lentiviral Vectors for Gene Therapy
Cesana, D., Volpin, M., Secanechia, Y. N. S., & Montini, E. (2017) · Springer eBooks · doi:10.1007/978-3-319-53457-2_2 · Cited by 9 · see citing works
Rinzema, N. J., Sofiadis, K., Tjalsma, S. J. D., Verstegen, M. J. A. M., Oz, Y., Valdes-Quezada, C., Felder, A.-K., Filipovska, T., van der Elst, S., de Andrade dos Ramos, Z., et al. (2021) · doi:10.1101/2021.10.05.463209 · Cited by 8 · see citing works
Globin vector regulatory elements are active in early hematopoietic progenitor cells
Cabriolu, A., Odak, A., Zamparo, L., Yuan, H., Leslie, C. S., & Sadelain, M. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.02.028 · Cited by 8 · see citing works
“from a human genome scan for high-occupancy CTCF recognition sequences that displayed potent enhancer-blocking activity in vitro and in vivo in a spontaneous tumor model where it reduced the risk of vector-induced genotoxicity.(20) These features, as well as its small size, informed our selection of A1 over previously…”
BackgroundPapayanni, P. G., Psatha, N., Christofi, P., Li, X., Melo, P., Volpin, M., Montini, E., Liu, M., Kaltsounis, G., Yiangou, M., et al. (2021) · Human Gene Therapy · doi:10.1089/hum.2021.142 · Cited by 8 · see citing works
“26 Importantly, their compact size (119–284 bp) implicates accommodation capacity by all gene therapy vectors, avoiding detrimental effects on viral titers.”
InfluentialCarlson, C. K., Loveless, T. B., Milisavljevic, M., Kelly, P. I., Mills, J. H., Tyo, K. E. J., & Liu, C. C. (2024) · ACS Synthetic Biology · doi:10.1021/acssynbio.4c00414 · Cited by 7 · see citing works
Large-scale discovery of potent, compact and erythroid specific enhancers for gene therapy vectors
Psatha, N., Sova, P., Georgolopoulos, G., Paschoudi, K., Iwata, M., Bloom, J. E., Ulyanova, T., Wang, H., Kirtsou, A., Vasiloudis, N.-I., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59235-x · Cited by 7 · see citing works
Pushing the TAD boundary: Decoding insulator codes of clustered CTCF sites in 3D genomes
Huang, H., & Wu, Q. (2024) · BioEssays · doi:10.1002/bies.202400121 · Cited by 7 · see citing works
Generation of targeted homozygosity in the genome of human induced pluripotent stem cells
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“33,34 Genome editing may eliminate the risk of near random viral vector integration and insertional mutagenesis, of gene addition by viral vectors, but it faces the risk of unintended ‘‘off target’’ mutagenesis that could generate nonspecific and undesirable genetic modifications with unexpected…”
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“Tens of insulators have been assayed at a time, 24–28 and many tested fly or mammalian IBP sites were suggested to lack insulator activity.”
Epigenetic Regulation of Erythropoiesis: From Developmental Programs to Therapeutic Targets
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“Other insulating elements, of human origin, better efficiency and smaller size have been recently proposed [177,178].”
Novel photoreceptor-specific promoters for gene therapy in mid- to late-stage retinal degeneration
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“A growing body of evidence shows that the incorporation in the transferred unit of a class of specialized cis -regulatory elements known as chromatin insulators can reduce vector– genome reciprocal interactions, mitigating both vector silencing and vector-mediated genotoxicity [13,24–27].”
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“22,67,68 In this regard, a naturally occurring insulator in AAVS1 69 may confer the robust expression often reported from this site 70 (Figures 2C and 4D).”
Epigenetic Regulation of Macrophage Polarization
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“…Insulator on Aberrant Vector Transcription Cytogenet Genome Res 2017;151:72–81 DOI: 10.1159/000464315 73 tion [Ryu et al., 2007; Zychlinski et al., 2008; Arumugam et al., 2009; Montini et al., 2009; Hanawa et al., 2009; Li et al., 2009; Biasco et al., 2012; Liu et al., 2015; David et al., 2017].”
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Recombinant adeno-associated viruses as a gene delivery vehicle for the use in molecular medicine
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Light-Guided Rabies Virus Tracing for Neural Circuit AnalysisPreprint
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The Emerging Potential for Epigenetic Therapeutics in Noncancer Disorders
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TRIP through the chromatin: A high throughput exploration of enhancer regulatory landscapes
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- Authors
- Liu, M., Maurano, M. T., Wang, H., Qi, H., Song, C.-Z., Navas, P. A., Emery, D. W., Stamatoyannopoulos, J. A., & Stamatoyannopoulos, G.
- Affiliations
- University of Washington (US)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Stamatoyannopoulos, George
- Venue
- Nature Biotechnology
- Published
- 2015-01-12
- Volume
- 33
- Issue
- 2
- Pages
- 198-203
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W1975777043
- Cited by
- 121
- References
- 50
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 12 · 2023: 9 · 2022: 8 · 2021: 19 · 2020: 5 · 2019: 15 · 2018: 8 · 2017: 7 · 2016: 14 · 2015: 11
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL053750, P01 HL53750)
- National Institute of Mental Health (F31MH094073)
- National Human Genome Research Institute (U54HG007010, R90HG004152)
- National Institute of Environmental Health Sciences (U01ES017156)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- chromatin insulators, CTCF, enhancer blocking, gene therapy safety, insertional mutagenesis, genotoxicity, DNase I hypersensitive sites, viral vectors, hematologic malignancies, human genome
- MeSH terms
- CCCTC-Binding Factor, Binding Sites, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Genetic Vectors, Humans, Repressor Proteins, Genetic Therapy, Genome, Human, Sequence Analysis, DNA, Computational Biology, Genomics, Insulator Elements
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