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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Background
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Warren, J. A., Mastroeni, P., Dougan, G., Noursadeghi, M., Cohen, J., Walport, M. J., & Botto, M. (2002) · Infection and Immunity · doi:10.1128/iai.70.2.551-557.2002 · Cited by 53
Digital Genotyping of Macrosatellites and Multicopy Genes Reveals Novel Biological Functions Associated with Copy Number Variation of Large Tandem Repeats
Brahmachary, M., Guilmatre, A., Quilez, J., Hasson, D., Borel, C., Warburton, P. E., & Sharp, A. J. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004418 · Cited by 53
“A similar phenomenon termed repeat induced gene silencing has been observed in several transgenic organisms [43–45].”
Background
Production of transgenic piglets using ICSI–sperm-mediated gene transfer in combination with recombinase RecA
García‐Vázquez, F. A., Ruíz, S., Matás, C., Izquierdo-Rico, M. J., Grullón, L. A., Ondiz, A. D., Vieira, L. A., Avilés-López, K., Gutiérrez‐Adán, A., & Gadea, J. (2010) · Reproduction · doi:10.1530/rep-10-0129 · Cited by 52
“because they often have the potential to generate aberrant RNAs that can cause gene silencing (Garrick et al. 1998).”
Background
Postnatal development- and age-related changes in DNA-methylation patterns in the human genome
Salpea, P., RUSSANOVA, V. R., Hirai, T. H., Sourlingas, T. G., Sekeri‐Pataryas, K. E., Romero, R. J., Epstein, J., & Howard, B. H. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks312 · Cited by 51
CRISPR/Cas-mediated knock-in via non-homologous end-joining in the crustacean Daphnia magna
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IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells
Buanec, H. L., Gougeon, M., Mathian, A., Lebon, P., Dupont, J., Peltre, G., Hémon, P., Schmid, M., Bizzini, B., Künding, T., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113301108 · Cited by 52
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“The well established association of satellite repeats with heterochromatin (1–8) and the fact that repeats per se can induce gene silencing ( 14 ,15) strongly suggest that the proximal satellite sequences in 10q11, and the intervening duplicated sequences, would be heterochromatic in nature.”
Background
Helper‐independent and AAV‐ITR‐independent chromosomal integration of double‐stranded linear DNA vectors in mice
Nakai, H., Montini, E., Fuess, S., Storm, T. A., Meuse, L., Finegold, M., Grompe, M., & Kay, M. A. (2003) · Molecular Therapy · doi:10.1016/s1525-0016(02)00023-0 · Cited by 52
“The mechanisms of transgene silencing have not been elucidated yet; however, it may be attributed to the presence of adjoining plasmid backbone [12] or vector genome concatemerization [20].”
Background
Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival
Mannoor, K., Matejuk, A., Xu, Y., Beardall, M. K., & Chen, C. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102859 · Cited by 51
Fast identification of reliable hosts for targeted cell line development from a limited‐genome screening using combined φC31 integrase and CRE‐Lox technologies
Crawford, Y., Zhou, M., Hu, Z., Joly, J. C., Snedecor, B., Shen, A. Y., & Gao, A. E. (2013) · Biotechnology Progress · doi:10.1002/btpr.1783 · Cited by 51
“These repeats can lead to chromosomal rearrangement (deletion or translocation) and=or silencing via repeat-induced promoter methylation.(3,4) Consequently, some clones might become unstable over time despite the presence of constant selective pressure.”
Background
Genotypic and Phenotypic Characterization of P23H Line 1 Rat Model
Orhan, E., Dalkara, D., Neuillé, M., Lechauve, C., Michiels, C., Picaud, S. A., Léveillard, T., Sahel, J., Naash, M. I., LaVail, M. M., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127319 · Cited by 57
“Intrinsic silencing effect of multiple-copy tandem repeats on transgene expression could also be an explanation, since transcription inhibition can occur when more than 5 copies of the transgene are present [37, 38].”
Background
Analysis of Mice with Single and Multiple Copies of Transgenes Reveals a Novel Arrangement for the λ 5-V preB1 Locus Control Region
Sabbattini, P. M. R., Georgiou, A., Sinclair, C., & Dillon, N. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.1.671 · Cited by 51
“An additional conclusion from our study relates to recent findings that suggest that arrangement in multiple-copy tandem repeats has an intrinsic silencing effect on transgene expression (9, 14).”
Result
Myb Transcription Factors and Light Regulate Sporulation in the Oomycete Phytophthora infestans
Xiang, Q., & Judelson, H. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092086 · Cited by 50
“Similar findings are reported in mammals and plants [55,56].”
Result
Metastable epialleles and their contribution to epigenetic inheritance in mammals
Bertozzi, T. M., & Ferguson‐Smith, A. C. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.08.002 · Cited by 50
Ocular Dominance Plasticity in Binocular Primary Visual Cortex Does Not Require C1q
Welsh, C. A., Stephany, C.-É., Sapp, R. W., & Stevens, B. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1011-19.2019 · Cited by 51
A Direct Repeat Sequence at theRasgrf1Locus and Imprinted Expression
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Histidine-Rich Glycoprotein Binds to DNA and FcγRI and Potentiates the Ingestion of Apoptotic Cells by Macrophages
Gorgani, N. N., Smith, B. A., Kono, D. H., & Theofilopoulos, A. N. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.9.4745 · Cited by 50
IgG Autoantibodies against Deposited C3 Inhibit Macrophage-Mediated Apoptotic Cell Engulfment in Systemic Autoimmunity
Kenyon, K. D., Cole, C., Crawford, F., Kappler, J. W., Thurman, J. M., Bratton, D. L., Boackle, S. A., & Henson, P. M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003468 · Cited by 49
In vivo evidence for apoptosis in the bone marrow in systemic lupus erythematosus
Hepburn, A. L., Lampert, I. A., Boyle, J. J., Horncastle, D. E., Ng, W., Layton, M., Vyse, T. J., Botto, M., & Mason, J. C. (2007) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2006.065003 · Cited by 49
On the Roles of Repetitive DNA Elements in the Context of a Unified Genomic‐Epigenetic System
von Sternberg, R. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04917.x · Cited by 48
A Transgenic Prox1-Cre-tdTomato Reporter Mouse for Lymphatic Vessel Research
Bianchi, R., Teijeira, Á., Proulx, S. T., Christiansen, A. J., Seidel, C. D., Rülicke, T., Mäkinen, T., Hägerling, R., Halin, C., & Detmar, M. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122976 · Cited by 49
“It is possible that the integration sites of founders with higher copy numbers are in genomic regions that disturbed their transcription, or the high copy number itself was responsible for repeat-induced silencing of the transgene [27, 28].”
Background
Acquisition and presentation of follicular dendritic cell–bound antigen by lymph node–resident dendritic cells
McCloskey, M., de Lafaille, M. A. C., Carroll, M. C., & Erlebacher, A. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20100354 · Cited by 49
Genome Engineering Using Site-Specific Recombinases
Kolb, A. F. (2002) · Cloning and Stem Cells · doi:10.1089/153623002753632066 · Cited by 49
“This has been shown to have a beneficial effect of transgene expression (Garrick et al., 1997).”
Switching between Epigenetic States at Pericentromeric Heterochromatin
Déjardin, J. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.09.003 · Cited by 47
“Repeat-induced heterochromatin formation has also been described in the mouse [74,75], but the Piwi/piRNA pathway is not functional in mammalian somatic cells, suggesting the existence of other mechanisms to trigger heterochromatin formation.”
Background
A Nuclear mtDNA Concatemer (Mega-NUMT) Could Mimic Paternal Inheritance of Mitochondrial Genome
Balciuniene, J., & Balciunas, D. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00518 · Cited by 49
“While a concatemer of 100+ copies could be considered unusually large, concatemers of such size range have been observed in animal transgenesis experiments (Garrick et al., 1998; McGrail et al., 2011; Yong et al., 2015).”
Background
A copy number variant is associated with a spectrum of pigmentation patterns in the rock pigeon (Columba livia)
Bruders, R., Hollebeke, H. F. V., Osborne, E. J., Kronenberg, Z. N., Maclary, E. T., Yandell, M. D., & Shapiro, M. D. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008274 · Cited by 44
Complement and the Kidney
Quigg, R. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.7.3319 · Cited by 49
The B Cell Receptor Itself Can Activate Complement to Provide the Complement Receptor 1/2 Ligand Required to Enhance B Cell Immune Responses In Vivo
Rossbacher, J., & Shlomchik, M. J. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20022042 · Cited by 49
Development and Selection of Edited B Cells in B6.56R Mice
Sekiguchi, D. R., Yunk, L., Gary, D., Charan, D., Srivastava, B., Allman, D., WEIGERT, M. G., & Prak, E. T. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.11.6879 · Cited by 48
Prolonged Apoptotic Cell Accumulation in Germinal Centers of Mer-Deficient Mice Causes Elevated B Cell and CD4+ Th Cell Responses Leading to Autoantibody Production
Khan, T. N., Wong, E. B., Soni, C., & Rahman, Z. S. M. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1200824 · Cited by 48
Tn5 Transposase-Mediated Mouse Transgenesis1
Suganuma, R., Pelczar, P., Spetz, J. F., Höhn, B., Yanagimachi, R., & Moisyadi, S. (2005) · Biology of Reproduction · doi:10.1095/biolreprod.105.044669 · Cited by 48
“Such transgene loci are not desirable, because they often have the potential to generate aberrant RNAs that can cause gene silencing [12].”
Immune Adherence Revisited: Novel Players in an Old Game
Hess, C., & Schifferli, J. A. (2003) · Physiology · doi:10.1152/nips.01425.2002 · Cited by 48
Complex patterns of inheritance of an imprinted murine transgene suggest incomplete germline erasure
Kearns, M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.17.3301 · Cited by 48
Stable Production of Human Insulin-like Growth Factor 1 (IGF-1) in the Milk of Hemi- and Homozygous Transgenic Rabbits Over Several Generations
Zinovieva, N., Lassnig, C., Schams, D., Besenfelder, U., Wolf, E., Müller, S., Frenyó, L. V., Seregi, J., Müller, M. M., & Brem, G. (1998) · Transgenic Research · doi:10.1023/a:1008831028620 · Cited by 48
“The underlying principles discussed include heterochromatic condensation of transgene concatemeres by repeat sequences (transgene copy numbers) and=or proximity to existing heterochromatin, strain specific modifier genes or transgene methylation patterns (Koetsier et al., 1996; Dorer, 1997; Garrick et al., 1998; Schwe…”
A Major Linkage Region on Distal Chromosome 4 Confers Susceptibility to Mouse Autoimmune Gastritis
Silveira, P. A., Baxter, A. G., Cain, W. E., & van Driel, I. R. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.9.5106 · Cited by 48
Promoter suppression in cultured mammalian cells can be blocked by the chicken β-globin chromatin insulator 5′HS4 and matrix/scaffold attachment regions11Edited by M. Yaniv
Villemure, J.-F., Savard, N., & Belmaaza, A. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.5015 · Cited by 48
Transgenic Mouse Methods and Protocols
Hofker, M. H., & van Deursen, J. M. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-974-1 · Cited by 48

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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