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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Sohn, S., Reid, S., Bowen, M., Corbex, E., Gall, L. L., Sidlauskaite, E., Hourdé, C., Morel, B., Mariot, V., & Dumonceaux, J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111377 · Cited by 3
“This hypomethylation can be the consequence of either a reduction in the D4Z4 copy number in the subtelomeric part of chromosome 4 [12,13] and/or mutations in epigenetic modifier genes, including SMCHD1, DNMT3b, and LRIF1 [14–16].”
Background
Chapter 6.3 Ethical implications of knock-out and transgenesistechniques for animal research
Houdebine, L. (1999) · Techniques in the behavioral and neural sciences · doi:10.1016/s0921-0709(99)80069-8 · Cited by 3
Reporter mice express green fluorescent protein at initiation of meiosis in spermatocytes
Brown, P. R., Odet, F., Bortner, C. D., & Eddy, E. M. (2014) · genesis · doi:10.1002/dvg.22830 · Cited by 3
“Transgenes often insert as concatemers and an inverse relationship between transgene copy number and transgene silencing was reported (Bao-Cutrona and Moral, 2009; Garrick et al., 1998).”
Background
Genetic Analysis of Synaptogenesis
Lu, C. S., & Vactor, D. V. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-397266-8.00104-6 · Cited by 3
RETRACTED: Properdin homeostasis requires turnover of the alternative complement pathway
Wu, X., Xu, T. Q., & Atkinson, J. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006608107 · Cited by 3
Retracted
Reporter Gene Silencing in Targeted Mouse Mutants Is Associated with Promoter CpG Island Methylation
Kirov, J. V., Adkisson, M., Nava, A. J., Cipollone, A., Willis, B., Engelhard, E. K., Lloyd, K. C. K., de Jong, P., & West, D. B. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134155 · Cited by 3
“Silencing has been problematic in the construction of vectors for random transgene insertion and expression in the creation of animal models since vectors are often inserted as concatemers and provoke silencing [3].”
Background
The changing role of cell culture in the generation of transgenic livestock
Whitelaw, B., Farini, E., & Webster, J. (1999) · Cytotechnology · doi:10.1023/a:1008044517150 · Cited by 3
Germ Cell-Specific Excision of loxP-Flanked Transgenes in Rainbow Trout Oncorhynchus mykiss1
Katayama, N., Kume, S., Hattori-Ihara, S., Sadaie, S., Hayashi, M., & Yoshizaki, G. (2016) · Biology of Reproduction · doi:10.1095/biolreprod.115.136929 · Cited by 3
“Reportedly, the number of transgene copies inserted into a host genome affects expression level of the transgene [44, 45]; moreover, the site of integration of the transgene into the host genome also affects both the level and the specificity of transgene expression [46].”
Inheritance and expression stability of transgene in transgenic animals
Kong, Q., & Zhong-Hua, L. I. U. (2011) · Hereditas (Beijing) · doi:10.3724/sp.j.1005.2011.00504 · Cited by 3
“DOI [47] Garrick D, Fierring S, Martin DIK, Whitelaw E.”
Background
Transgenic Studies in the Mouse: Improving the Technology Towards a Conditional Temporal and Spatial Approach
Ristevski, S. (2003) · Humana Press eBooks · doi:10.1385/1-59259-220-1:319 · Cited by 3
Use of Natural and Artificial Chromosome Vectors for Animal Transgenesis
Kuroiwa, Y., Tomizuka, K., & Ishida, I. (2004) · Humana Press eBooks · doi:10.1385/1-59259-434-4:207 · Cited by 3
Knockout Mice and Steroid Receptor Research
Flodby, P., Teglund, S., & Gustafsson, J.-Α. (2003) · Humana Press eBooks · doi:10.1385/1-59259-115-9:201 · Cited by 3
Expression and functional analyses of murine Pelota (Pelo) gene
Buyandelger, B. (2007) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-1304 · Cited by 3
Mouse models of tight junction physiology
Hou, J. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818647-3.00008-8 · Cited by 2
Uncovering Regulators of Heterochromatin Mediated Silencing Using a Zebrafish Transgenic Reporter
Calvird, A. E., Broniec, M. N., Duval, K. L., Higgs, A. N., Arora, V., Ha, L., Schouten, E. B., Crippen, A. R., McGrail, M. A., Laue, K., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.832461 · Cited by 2
“In mouse, it was reported that a concatemeric array of a lacZ marked transgene acquired high levels of 5-methylcytosine and produced limited lacZ expression, while reduction of the array to a single transgene unit restored expression (Garrick et al., 1998).”
Background
ASIS-Seq: Transgene Insertion Site Mapping by Nanopore Adaptive Sampling
Yu, C., Caothien, R. H., Pham, A., Tam, L., Alcantar, T. M., Bacarro, N., Reyes, J., Jackson, M., Nakao, B., & Roose‐Girma, M. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-2990-1_5 · Cited by 2
Tissue-specific silencing of integrated transgenes achieved through endogenous RNA interference in Caenorhabditis elegans
Chen, S., Liu, W., Xiong, L., Tao, Z., & Zhao, D. (2024) · RNA Biology · doi:10.1080/15476286.2024.2332856 · Cited by 2
“Most transgenes in animals and plants encounter rejection by the host, which is an important protective strategy for organisms [1–8].”
DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells
Rich, J., Bennaroch, M., Notel, L., Patalakh, P., Alberola, J., Issa, F., Opolon, P., Bawa, O., Rondof, W., Marchais, A., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00097-z · Cited by 2
“This observation aligns with prior research on the epigenetic regulation of DNA repeat silencing by KZFP (Imbeault et al, 2017; Turelli et al, 2020) and the role of DNA repeats in modulating gene expression (Garrick et al, 1998).”
Result
Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: Insights from transgenic mouse models
Yang, T., Hsu, Y., Yeh, P., Hung, C., Tsai, Y., Fang, M.-C., Yen, A. C. C., Chen, L., Pan, J.-Y., Wu, C., et al. (2024) · Hearing Research · doi:10.1016/j.heares.2024.109134 · Cited by 2
Oligonucleotide‐mediated gene editing is underestimated in cells expressing mutated green fluorescent protein and is positively associated with target protein expression
Disterer, P., Papaioannou, I., Evans, V. C., Simons, J. P., & Owen, J. S. (2012) · The Journal of Gene Medicine · doi:10.1002/jgm.1639 · Cited by 2
“regulation than a multi-copy gene array is unknown, although there is a clear precedent for variegated expression of multi-copy transgenes [34,39].”
Background
CENTB5 gene expression in humans and mice
Shubina, D. M., Олеговна, С. И., Сломинская, Н. А., Alenina, N. V., Bäder, M., & Patkin, E. L. (2009) · Molecular Biology · doi:10.1134/s0026893309030042 · Cited by 2
“It is known that intronic sequences can modulate the expression not only of the genes harboring them, but also of the neighboring and even rather remote ones [13, 29, 30]; therefore, the simultaneous analysis of CENTB 5 , SCNN 1 D , and ACOT 7 expression seems rather promising.”
BackgroundMethod
Replication allows inactivation of a knocked-in locus control region in inappropriate cell lineages
Menzel, U., Ktistaki, E., Tolaini, M., Veiga‐Fernandes, H., & Kioussis, D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010317107 · Cited by 2
“Although studies have been performed in which transgene copy numbers were reduced in situ, allowing the comparison of transgenic lines that differ in copy numbers in the same integration site, the random integration of a transgene remains amajor limitation in such analyses (17, 26, 27).”
Background
Modulation of Reporter EGFP Gene Expression by a Disease-Associated Human Intra-Intronic Minisatellite Upon Transient and Stable Transfection
Sasina, L. K., Fedorova, E. M., Грудинина, Н. А., Belotserkovskaya, E., Solovyov, K. V., Олеговна, С. И., & Patkin, E. L. (2013) · International Journal of Biological Engineering · Cited by 2
Modulation of the Murine CD8 Gene Complex Following the Targeted Integration of Human CD2-Locus Control Region Sequences
Menzel, U., Kosteas, T., Tolaini, M., Killeen, N. P., Roderick, K., & Kioussis, D. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100709 · Cited by 2
“Other approaches take advantage of the Cre/lox sitespecific recombination systems to reduce transgene copy numbers, as well as to allow direct comparison of transgenic lines with the same integration site but different copy numbers (7, 8).”
Background
Expression Engineering – The IE2 Promoter/Enhancer from Mouse CMV
Imhof, M. O., Chatellard, P., Kobr, M., Pankiewicz, R., Duverger, V., Bagnoud, L., Sauvage, C., & Mossu, C. (2009) · Cell engineering · doi:10.1007/978-90-481-2245-5_2 · Cited by 2
“Furthermore, the repetitive arrangement of the same expression promoting sequences could result in instable expression through repeat-induced silencing in stably transfected cells (Garrick et al., 1998; McBurney et al., 2002).”
Background
Chimerism in piglets developed from aggregated cloned embryos
Huang, Y., Li, Z., Wang, A., Han, X., Song, Y., Yuan, L., Li, T., Wang, B., Lai, L., Ouyang, H., et al. (2016) · FEBS Open Bio · doi:10.1002/2211-5463.12037 · Cited by 2
Comparison of two related lines of tauGFP transgenic mice designed for lineage tracing
Sharp, L., Pratt, T., MacKay, G. E., Keighren, M., Flockhart, J. H., Chandler, E. J., Price, D. J., Mason, J. O., & West, J. D. (2017) · BMC Developmental Biology · doi:10.1186/s12861-017-0149-x · Cited by 2
“Transgene silencing can occur if the transgene integrates near an endogenous heterochromatic site [41], which may prevent the transcriptional machinery from accessing the transgene, or if it triggers the formation of heterochromatin by integrating as a series of repeated copies [45, 46].”
Background
Chromosomal Position Effects and Gene Variegation
Schluth‐Bolard, C., Ottaviani, A., Gilson, É., & Magdinier, F. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-375709-8.00006-x · Cited by 3
Transgenic and Genetic Animal Models
Keri, R. A., & Siegel, R. E. (2009) · Elsevier eBooks · doi:10.1016/b978-008088783-8.00085-1 · Cited by 2
Transgene Design
van de Sluis, B., & Voncken, J. W. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-974-1_6 · Cited by 2
19 DIRECT INTRODUCTION OF GENE CONSTRUCTS INTO THE PRONUCLEUS-LIKE STRUCTURE OF CLONED EMBRYOS: A NEW STRATEGY FOR THE GENERATION OF GENETICALLY MODIFIED PIGS
Kurome, M., Leuchs, S., Keßler, B., Kemter, E., Jemiller, E., Zakhartchenko, V., & Wolf, E. (2015) · Reproduction Fertility and Development · doi:10.1071/rdv28n2ab19 · Cited by 2
The impact of a transgene for ovine growth hormone on the performance of two breeds of sheep1
Adams, N. R., Briegel, J. R., & Ward, K. A. (2002) · Journal of Animal Science · doi:10.1093/ansci/80.9.2325 · Cited by 2
Nuclear RNA Silencing and Related Phenomena in Animals
Malı́k, R., & Svoboda, P. (2012) · doi:10.1002/9781118349045.ch15 · Cited by 2
Transgenic Analysis of the Proopiomelanocortin Neuroendocrine System
Low, M. J., Rubinstenin, M., & Chan, E. (2001) · Humana Press eBooks · doi:10.1007/978-1-59259-102-2_15 · Cited by 2
Chromosome Assignment of Cd36 Transgenes in Two Rat SHR Lines by FISH and Linkage Mapping of Transgenic Insert in the SHR-TG19 Line
Liška, F., Levan, G., Helou, K., Sladká, M., Pravenec, M., Zı́dek, V., Landa, V., & Křen, V. (2002) · Folia Biologica · doi:10.14712/fb2002048040139 · Cited by 2
Generating in vivo somatic mouse mosaics with locus-specific, stably-integrated transgenic elementsPreprint
Kim, G. B., Dutra‐Clarke, M., Levy, R., Park, H., Sabet, S., Molina, J., Akhtar, A. A., Bannykh, S., Danielpour, M., & Breunig, J. J. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/097386 · Cited by 2
“their unpredictable genomic integration patterns, subsequent insertional mutagenesis, and epigenetic transgene silencing (Akhtar et al., 2013; Garrick et al., 1998; Woods et al., 2003).”
Background

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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