Repeat-induced gene silencing in mammals

Garrick, David; Fiering, Steven; Martin, David I.K.; Whitelaw, Emma

doi:10.1038/ng0198-56

Cited by 890Animal Genetics and ReproductionEpigenetics and DNA MethylationChromosomal and Genetic Variations

Repeat-induced gene silencing in mammals

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

DOI 10.1038/ng0198-56

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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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The transgene integration site is neither centromeric nor telomeric, so the silencing is presumably related to the multicopy nature of the transgene array.
“This site of integration is neither centromeric nor telomeric, and so presumably the silencing is related to the multicopy nature of the transgene array [13,14].”
From A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development (2008) · cites this paper as [13]
Gene addition approaches with AAV are limited by transgene silencing.
“transgene silencing,4”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [4]

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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 › Agricultural and Biological Sciences › Plant Science › 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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