Cited by 889Animal Genetics and ReproductionEpigenetics and DNA MethylationChromosomal and Genetic Variations

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Repeat-induced gene silencing in mammals

Garrick, David, Fiering, Steven, Martin, David I.K., Whitelaw, Emma·1998·Nature Genetics

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Abstract

In both plants and Drosophila melanogaster, expression from a transgenic locus may be silenced when repeated transgene copies are arranged as a concatameric array. This repeat-induced gene silencing is frequently manifested as a decrease in the proportion of cells that express the transgene, resulting in a variegated pattern of expression. There is also some indication that, in transgenic mammals, the number of transgene copies within an array can exert a repressive influence on expression, with several mouse studies reporting a decrease in the level of expression per copy as copy number increases. However, because these studies compare different sites of transgene integration as well as arrays with different numbers of copies, the expression levels observed may be subject to varying position effects as well as the influence of the multicopy array. Here we describe use of the lox/Cre system of site-specific recombination to generate transgenic mouse lines in which different numbers of a transgene are present at the same chromosomal location, thereby eliminating the contribution of position effects and allowing analysis of the effect of copy number alone on transgene silencing. Reduction in copy number results in a marked increase in expression of the transgene and is accompanied by decreased chromatin compaction and decreased methylation at the transgene locus. These findings establish that the presence of multiple homologous copies of a transgene within a concatameric array can have a repressive effect upon gene expression in mammalian systems.

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Position-independent, high-level expression of the human β-globin gene in transgenic mice
Grosveld, F. G., van Assendelft, G. B., Greaves, D. R., & Kollias, G. A. (1987) · Cell · doi:10.1016/0092-8674(87)90584-8 · Cited by 1,908
GERM-LINE TRANSFORMATION OF MICE
Palmiter, R. D., & Brinster, R. L. (1986) · Annual Review of Genetics · doi:10.1146/annurev.ge.20.120186.002341 · Cited by 1,157
Efficient in vivo manipulation of mouse genomic sequences at the zygote stage.
Lakso, M., Pichel, J. G., Gorman, J. R., Sauer, B., Okamoto, Y., Lee, E., Alt, F. W., & Westphal, H. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.12.5860 · Cited by 1,125
Reversible methylation and inactivation of marker genes in sequentially transformed tobacco plants
Matzke, M. A., Primig, M., Trnovsky, J., & Matzke, A. J. M. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb03421.x · Cited by 545
Expansions of transgene repeats cause heterochromatin formation and gene silencing in Drosophila
Dorer, D. R. (1994) · Cell · doi:10.1016/0092-8674(94)90439-1 · Cited by 504
The basics of basal transcription by RNA polymerase II
Buratowski, S. (1994) · Cell · doi:10.1016/0092-8674(94)90226-7 · Cited by 410
A major positive regulatory region located far upstream of the human alpha-globin gene locus.Preprint
Higgs, D. R., Wood, W. G., Jarman, A. P., Sharpe, J. A., Lida, J., Pretorius, I., & Ayyub, H. (1990) · Genes & Development · doi:10.1101/gad.4.9.1588 · Cited by 335
Suppression of beta‐1,3‐glucanase transgene expression in homozygous plants.
de Carvalho‐Niebel, F., Gheysen, G., Kushnir, S., MONTAGU, M. V., Inzé, D., & Castresana, C. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05324.x · Cited by 304
Site-specific recombination of a transgene in fertilized eggs by transient expression of Cre recombinase.
Araki, K., Araki, M., Miyazaki, J., & VASSALLI, P. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.1.160 · Cited by 284
Epigenetic changes in the expression of the maize A1 gene inPetunia hybrida: Role of numbers of integrated gene copies and state of methylation
Linne, F., Heidmann, I., Saedler, H., & Meyer, P. (1990) · Molecular and General Genetics MGG · doi:10.1007/bf00633837 · Cited by 281

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Remy, S., Tesson, L., Ménoret, S., Usal, C., Cian, A. D., Thépenier, V., Thinard, R., Baron, D., Charpentier, M., Renaud, J.-B., et al. (2014) · Genome Research · doi:10.1101/gr.171538.113 · Cited by 47
“Although transgenic animals with RI in concatemers are subject to gene silencing (Garrick et al. 1998), expression of GFP was equivalent in our rats harboring a profile with and without concatemers in the Rosa26 locus.”
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Buck, S. D., Peck, I., Wilde, C. D., Marjanac, G., Nolf, J., Paepe, A. D., & Depicker, A. (2007) · PLANT PHYSIOLOGY · doi:10.1104/pp.107.104067 · Cited by 46
“Similarly, in transgenic mice, a CRE/loxP resolution strategy resulted not only in a reduced copy number but also in a marked increase in transgene expression (Garrick et al., 1998).”
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Pelczar, P., Kalck, V., Gomez, D., & Höhn, B. (2004) · EMBO Reports · doi:10.1038/sj.embor.7400165 · Cited by 46
“Ideally, a DNA delivery system should be efficient, at the same time avoiding integration of multiple transgene copies, as this frequently leads to gene silencing (Garrick et al, 1998).”
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“Not all the functional deficiencies of endogenous genes can be compensated for by other genes, whereas transgene silencing is a prevalent problem, especially when genes integrate as multicopy transgene arrays (Garrick et al., 1998; McBurney et al., 2002; Muskens et al., 2000).”
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Self-citation
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Saitoh, Y., Miyamoto, N., Okada, T., Gondo, Y., Showguchi-Miyata, J., Hadano, S., & Ikeda, J. (2000) · Genomics · doi:10.1006/geno.2000.6261 · Cited by 37
Optimisation of tomato Micro-tom regeneration and selection on glufosinate/Basta and dependency of gene silencing on transgene copy number
Khuong, T. T. H., Crété, P., Robaglia, C., & Caffarri, S. (2013) · Plant Cell Reports · doi:10.1007/s00299-013-1456-8 · Cited by 36
Autoreactive MZ and B-1 B-cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance
Qian, Y., Conway, K. L., Lu, X., Seitz, H., Matsushima, G. K., & Clarke, S. H. (2006) · Blood · doi:10.1182/blood-2005-12-006858 · Cited by 36
MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses
Grönwall, C., Chen, Y., Vas, J., Khanna, S., Thiel, S., Corr, M., Kono, D. H., & Silverman, G. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211868109 · Cited by 36
Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated I B
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Integration, stability and expression of the E. coli phytase transgene in the Cassie line of Yorkshire Enviropig™
Forsberg, C. W., Meidinger, R. G., Liu, M., Cottrill, M., Golovan, S. P., & Phillips, J. P. (2012) · Transgenic Research · doi:10.1007/s11248-012-9646-7 · Cited by 36
“1981) and copy number may not be related to expression levels (Garrick et al. 1998).”
Requirement for complement in antibody responses is not explained by the classic pathway activator IgM
Rutemark, C., Alicot, E., Bergman, A., Ma, M.-H., Getahun, A., Ellmerich, S., Carroll, M., & Heyman, B. (2011) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1109831108 · Cited by 47
Novel Cell Lines Promote the Discovery of Genes Involved in Early Heart Development
Brunskill, E. W., Witte, D. P., Yutzey, K. E., & Potter, S. S. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0313 · Cited by 36
Pest Control by the Introduction of a Conditional Lethal Trait on Multiple Loci: Potential, Limitations, and Optimal Strategies
Schliekelman, P., & Gould, F. L. (2000) · Journal of Economic Entomology · doi:10.1603/0022-0493-93.6.1543 · Cited by 36
“The phenomenon of gene silencing has beendocumented inmost detail for plants (Vaucheret et al. 1998, Grant 1999), but it has also been observed in mice (Garrick et al. 1998) and Drosophila (PalBhadra et al. 1997,Birchler et al. 1999).”
Background
Mice Lacking C1q Are Protected from High Fat Diet-induced Hepatic Insulin Resistance and Impaired Glucose Homeostasis
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AAV-Mediated Gene Targeting Is Significantly Enhanced by Transient Inhibition of Nonhomologous End Joining or the Proteasome In Vivo
Paulk, N. K., Loza, L. I. M., Finegold, M. J., & Grompe, M. (2012) · Human Gene Therapy · doi:10.1089/hum.2012.038 · Cited by 35
“Yet, drawbacks to this methodology abound including unregulated and transient episomal expression (Garrick et al., 1998; Russell and Kay, 1999), random integration (Hendrie et al., 2003), increased oncogenic risks (Donsante et al., 2007), and the inability to treat genetically dominant disorders…”
Background
Transgenic mouse overexpressing the Akt reduced the volume of infarct area after middle cerebral artery occlusion
Ohba, N., Kiryu‐Seo, S., Maeda, M., Muraoka, M., Ishii, M., & Kiyama, H. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.02.029 · Cited by 35
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Ferry, H., Potter, P. K., Crockford, T. L., Nijnik, A., Ehrenstein, M. R., Walport, M. J., Botto, M., & Cornall, R. J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.5.2916 · Cited by 35
TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines
Schwartz, J. L., Jordan, R. T., Liber, H. L., Murnane, J. P., & Evans, H. H. (2001) · Genes Chromosomes and Cancer · doi:10.1002/1098-2264(2000)9999:9999 · Cited by 27
Transgene constructs in coho salmon (Oncorhynchus kisutch) are repeated in a head-to-tail fashion and can be integrated adjacent to horizontally-transmitted parasite DNA
Uh, M., Khattra, J. S., & Devlin, R. H. (2006) · Transgenic Research · doi:10.1007/s11248-006-9016-4 · Cited by 34
“For example, transgene expression has been found to be highly correlated with copy number in some cases, but can be associated with heterochromatin and gene silencing when arranged in large tandem arrays (Knotts et al. 1995; Garrick et al. 1998 ).”
Background
Optimized Selection Marker and CHO Host Cell Combinations for Generating High Monoclonal Antibody Producing Cell Lines
Yeo, J. H. M., Ho, S. C. L., Mariati, M., Koh, E. Y. C., Tay, S. J., Woen, S., Zhang, P., & Yang, Y. (2017) · Biotechnology Journal · doi:10.1002/biot.201700175 · Cited by 36
Repeated integration of antibody genes into a pre-selected chromosomal locus of CHO cells using an accumulative site-specific gene integration system
Kawabe, Y., Makitsubo, H., Kameyama, Y., Huang, S., Itô, A., & Kamihira, M. (2011) · Cytotechnology · doi:10.1007/s10616-011-9397-y · Cited by 35
Development of autoimmunity in mice lacking DNA topoisomerase 3β
Kwan, K. Y., Greenwald, R. J., Mohanty, S., Sharpe, A. H., Shaw, A. C., & Wang, J. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703587104 · Cited by 34
Astrocyte Specificity and Coverage of hGFAP-CreERT2 [Tg(GFAP-Cre/ERT2)13Kdmc] Mouse Line in Various Brain Regions
Park, Y. M., Chun, H., Shin, J.-I., & Lee, C. J. (2018) · Experimental Neurobiology · doi:10.5607/en.2018.27.6.508 · Cited by 33
Variegated Expression of the Endogenous Immunoglobulin Heavy-Chain Gene in the Absence of the Intronic Locus Control Region
Ronai, D., Berrú, M., & Shulman, M. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.10.7031 · Cited by 34
“Repeated DNA segments can themselves induce variegation (10, 14 ), and the variegated expression of transgenes can sometimes result from their insertion as a tandem array.”
Background
A Novel Role of Complement Factor C1q in Augmenting the Presentation of Antigen Captured in Immune Complexes to CD8+ T Lymphocytes
van Montfoort, N., de Jong, J. M. H., Schuurhuis, D. H., van der Voort, E. I. H., Camps, M. G. M., Huizinga, T. W. J., van Kooten, C., Daha, M. R., Verbeek, J. S., OSSENDORP, F. A., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.12.7581 · Cited by 33
Incomplete penetrance and variable expressivity: is there a microRNA connection?
Ahluwalia, J. K., Hariharan, M., Bargaje, R., Pillai, B., & Brahmachari, V. (2009) · BioEssays · doi:10.1002/bies.200900066 · Cited by 31
“This discordance is correlated with copy number, the status of DNA, and histone methylation at the site-of-integration of the transgene.((23,24))”
Background
NF-E2-mediated enhancement of megakaryocytic differentiation and platelet production in vitro and in vivo
Fock, E.-L., Feng, Y., Pan, S., & Chong, B. H. (2007) · Experimental Hematology · doi:10.1016/j.exphem.2007.08.015 · Cited by 33
PITT: Pronuclear Injection-Based Targeted Transgenesis, a Reliable Transgene Expression Method in Mice
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“in some cases, low or silenced transgene expression is reported in transgenic mice with high-copy-number arrays of transgene, and a reduction in the copy number in these mice resulted in a significant increase in transgene expression [22].”
Transcriptome Analysis of Targeted Mouse Mutations Reveals the Topography of Local Changes in Gene Expression
West, D. B., Engelhard, E. K., Adkisson, M., Nava, A. J., Kirov, J. V., Cipollone, A., Willis, B., Rapp, J., de Jong, P. J., & Lloyd, K. C. K. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1005691 · Cited by 31
“In addition, targeting vectors into safe havens with open chromatin [7] ensures that other genes are not disrupted and the targeting eliminates concatenation of the vector which may produce silencing [8].”
Background
Considerations for the use of Cre recombinase for conditional gene deletion in the mouse lens
Lam, P. T., Padula, S. L., Hoang, T. V., Poth, J. E., Liu, L., Liang, C., LeFever, A. S., Wallace, L. M., Ashery‐Padan, R., Riggs, P. K., et al. (2019) · Human Genomics · doi:10.1186/s40246-019-0192-8 · Cited by 30
Gene Amplification and the Extrachromosomal Circular DNA
Shimizu, N. (2021) · Genes · doi:10.3390/genes12101533 · Cited by 34
“Another problem was that the amplification produced an ordered tandem repeat, which was subjected to repeat-induced gene silencing (RIGS; [62,63]).”
Background
Conditional activation of a single‐copy L1 transgene in mice by Cre
An, W., Han, J. S., Schrum, C. M., Maitra, A., Köentgen, F., & Boeke, J. D. (2008) · genesis · doi:10.1002/dvg.20407 · Cited by 30
The trans-silencing capacity of invertedly repeated transgenes depends on their epigenetic state in tobacco
Fojtová, M. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl180 · Cited by 33
“The reduction in expression seems to depend on dosage because plants with greater hypomethylation (2,5) had lower nptII RNA accumulation levels compared with plants with a lower degree of hypomethylation (1,3,4).”
Background
Essential Role of Factor B of the Alternative Complement Pathway in Complement Activation and Opsonophagocytosis during Acute Pneumococcal Otitis Media in Mice
Li, Q., Li, Y. X., Stahl, G. L., Thurman, J. M., He, Y., & Tong, H. H. (2011) · Infection and Immunity · doi:10.1128/iai.00168-11 · Cited by 32
Transcription-dependent silencing of inducible convergent transgenes in transgenic mice
Calero‐Nieto, F. J., Bert, A. G., & Cockerill, P. N. (2010) · Epigenetics & Chromatin · doi:10.1186/1756-8935-3-3 · Cited by 32
“One of the major problems facing transgenic mouse model systems is that transgenes frequently undergo silencing [1-3].”
BackgroundInfluential
Tetracycline-Inducible System for Regulation of Skeletal Muscle-Specific Gene Expression in Transgenic Mice
Grill, M. A., Bales, M. A., Fought, A. N., Rosburg, K. C., Munger, S. J., & Antin, P. B. (2003) · Transgenic Research · doi:10.1023/a:1022119005836 · Cited by 32
The Suppressor‐mutator element and the evolutionary riddle of transposons
Fedoroff, N. V. (1999) · Genes to Cells · doi:10.1046/j.1365-2443.1999.00233.x · Cited by 32
“inactivation mechanism similar to that in plants is now known to exist in animals (Garrick et al. 1998).”
Background
Targeting of a histone acetyltransferase domain to a promoter enhances protein expression levels in mammalian cells
Kwaks, T., Sewalt, R. G. A. B., van Blokland, R., Siersma, T. K., Kasiem, M. M. A., Kelder, A., & Otte, A. P. (2004) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2004.07.012 · Cited by 30
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Lötscher, M., Recher, M., Hunziker, L., & Klein, M. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.12.6040 · Cited by 32
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Fan, H., Longacre, A., Meng, F., Patel, V. A., Hsiao, K., Koh, J. S., & Levine, J. S. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.8.4834 · Cited by 32
Apoptotic Splenocytes Drive the Autoimmune Response to Poly(ADP-ribose) Polymerase 1 in a Murine Model of Lupus
Grader‐Beck, T., Casciola-Rosen, L. A., Lang, T. J., Puliaev, R., Rosen, A., & Via, C. S. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.1.95 · Cited by 32
Gene silencing
Wassenegger, M. (2002) · International review of cytology · doi:10.1016/s0074-7696(02)19011-5 · Cited by 32

Authors: Garrick, D., Fiering, S., Martin, D. I. K., & Whitelaw, E.
Affiliations: The University of Sydney (AU)
Dartmouth–Hitchcock Medical Center (US)
Fred Hutch Cancer Center (US)
ORCID: Fiering, Steven
Whitelaw, Emma
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 1998-01
Volume: 18
Issue: 1
Pages: 56-59
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng0198-56
OpenAlex: W2065189089
Cited by: 887
References: 32
Citations by year: 2026: 4 · 2025: 3 · 2024: 20 · 2023: 16 · 2022: 9 · 2021: 16 · 2020: 16 · 2019: 14 · 2018: 20 · 2017: 23 · 2016: 25 · 2015: 28 · 2014: 24 · 2013: 24 · 2012: 41
FWCI: 36.14
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
Keywords: transgene copy number, transgene silencing, position effect, transgenic mice, chromatin condensation, DNA methylation, epigenetic silencing
MeSH terms: Animals, Chromatin, Erythrocytes, Female, Gene Expression Regulation, Humans, Lac Operon, Male, Mammals, Mice, Transgenic, Repetitive Sequences, Nucleic Acid, Transcription, Genetic, Viral Proteins, Gene Dosage, Transgenes, Integrases, Mice

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Repeat-induced gene silencing in mammals

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