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

The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.

Repeat-induced gene silencing in mammals

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/ng0198-56

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

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

Flagged first, then by citations

Show all 32 references

Sorted by citations

Items 101–200 of 889

Role of Complement Component C1q in the Onset of Preeclampsia in Mice
Singh, J. K., Ahmed, A., & Girardi, G. (2011) · Hypertension · doi:10.1161/hypertensionaha.111.175919 · Cited by 189
An Inverted Repeat Triggers Cytosine Methylation of Identical Sequences in Arabidopsis
Luff, B., Pawlowski, L., & Bender, J. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80478-5 · Cited by 187
DNA demethylation
Wolffe, A. P., Jones, P. L., & Wade, P. A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.11.5894 · Cited by 185
Promoter Elements of vav Drive Transgene Expression In Vivo Throughout the Hematopoietic Compartment
Ogilvy, S., Metcalf, D., Gibson, L., Bath, M. L., Harris, A. W., & Adams, J. M. (1999) · Blood · doi:10.1182/blood.v94.6.1855 · Cited by 183
Gene silencing as a threat to the success of gene therapy
Bestor, T. H. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9459 · Cited by 182
“(14) showed that a repeat array upstream of a reporter gene in transgenic mice caused methylation and silencing of the transgene; removal of the array via Cre-mediated excision relieved the silencing and reduced methylation of the transgene promoter.”
Background
Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation
Beers, S. A., Chan, H. T. C., James, S., French, R. R., Attfield, K. E., Brennan, C. M., Ahuja, A., Shlomchik, M. J., Cragg, M. S., & Glennie, M. J. (2008) · Blood · doi:10.1182/blood-2008-04-149161 · Cited by 180
Transgenerational analysis of transcriptional silencing in zebrafish
Akitake, C. M., Macurak, M., Halpern, M. E., & Goll, M. G. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.01.002 · Cited by 181
“The link between silencing and repetitive DNA was elegantly demonstrated by Garrick et al. (Garrick et al., 1998) who established a mouse line carrying approximately 100 repeats of an erythroid-specific LacZ transgene flanked by loxP sites.”
BackgroundInfluential
C1q and HMGB1 reciprocally regulate human macrophage polarization
Son, M., Porat, A., He, M., Suurmond, J., Santiago‐Schwarz, F., Andersson, U., Coleman, T. R., Volpe, B. T., Tracey, K. J., Al‐Abed, Y., et al. (2016) · Blood · doi:10.1182/blood-2016-05-719757 · Cited by 182
The marks, mechanisms and memory of epigenetic states in mammals
Rakyan, V. K., Preis, J. I., Morgan, H. D., & Whitelaw, E. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3560001 · Cited by 182
Self-citation
Blockade of Notch1 Signaling Alleviates Murine Lupus via Blunting Macrophage Activation and M2b Polarization
Zhang, W., Xu, W., & Xiong, S. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904016 · Cited by 177
Inhibition of Phosphatidylserine Recognition Heightens the Immunogenicity of Irradiated Lymphoma Cells In Vivo
Bondanza, A., Zimmermann, V. S., Rovere, P. Q., Turnay, J., Dumitriu, I. E., Stach, C. M., Voll, R. E., Gaipl, U. S., Bertling, W. M., Pöschl, E., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040327 · Cited by 176
Protective immune responses against West Nile virus are primed by distinct complement activation pathways
Mehlhop, E., & Diamond, M. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052388 · Cited by 175
Transposons and genome evolution in plants
Fedoroff, N. V. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.13.7002 · Cited by 173
Heterochromatin function in complex genomes
Henikoff, S. (2000) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(99)00034-7 · Cited by 173
Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia
Schäfer, M. K.-H., Schwaeble, W., Post, C., Salvati, P., Calabresi, M., Sim, R. B., Petry, F., Loos, M., & Weihe, E. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.10.5446 · Cited by 172
C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity
Benoit, M. E., Hernandez, M. X., Dinh, M. L., Benavente, F., Vasquez, O., & Tenner, A. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.400168 · Cited by 155
Transgene silencing in monocots
Iyer, L. M., Kumpatla, S. P., Chandrasekharan, M. B., & Hall, T. C. (2000) · Plant Molecular Biology · doi:10.1023/a:1006412318311 · Cited by 168
“While the events depicted by the highlighted layers in Figure 1 presumably arose in response to individual situations and stimuli, each contributes to the overall integrity of the genome and represents a potential barrier to the insertion of functional transgenes.”
Background
Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells
Potter, P. K., Cortés-Hernández, J., Quartier, P., Botto, M., & Walport, M. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.6.3223 · Cited by 167
A muscle-specific transgenic reporter line of the sea anemone, Nematostella vectensis
Renfer, E., Amon-Hassenzahl, A., Steinmetz, P. R. H., & Technau, U. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909148107 · Cited by 164
“than high copy numbers generated by plasmid injection (18, 19).”
Background
Role of inverted DNA repeats in transcriptional and post-transcriptional gene silencing
Muskens, M., Vissers, A. P. A., Mol, J. N. M., & Kooter, J. M. (2000) · Plant Molecular Biology · doi:10.1023/a:1006491613768 · Cited by 165
“Similar findings have been described for transgene repeats in mammals (Garrick et al., 1998), indicating that RIGS is a conserved HDGS mechanism.”
Glucocorticoid Augmentation of Macrophage Capacity for Phagocytosis of Apoptotic Cells Is Associated with Reduced p130Cas Expression, Loss of Paxillin/pyk2 Phosphorylation, and High Levels of Active Rac
Giles, K. M., Ross, K. A., Rossi, A. G., Hotchin, N. A., Haslett, C., & Dransfield, I. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.2.976 · Cited by 167
Plants as bioreactors for protein production: avoiding the problem of transgene silencing
Wilde, C. D., Houdt, H. V., Buck, S. D., Angenon, G., Jaeger, G. D., & Depicker, A. (2000) · Plant Molecular Biology · doi:10.1023/a:1006464304199 · Cited by 164
“A promising technology to ensure that only a single copy of a transgene remains integrated into the plant genome uses site-specific recombination to resolve complex loci into single-copy transgenes (Garrick et al., 1998; Srivastavaet al., 1999); this technique could become an important tool for the”
BackgroundMethod
Maturation of dendritic cells abrogates C1q production in vivo and in vitro
Castellano, G., Woltman, A. M., Nauta, A. J., Roos, A., Trouw, L. A., Seelen, M. A., Schena, F. P., Daha, M. R., & van Kooten, C. (2004) · Blood · doi:10.1182/blood-2003-09-3046 · Cited by 165
Complement C4 Inhibits Systemic Autoimmunity through a Mechanism Independent of Complement Receptors Cr1 and Cr2
Chen, Z., Koralov, S. B., & Kelsoe, G. H. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.9.1339 · Cited by 164
C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells
Fraser, D. A., Laust, A. K., Nelson, E. L., & Tenner, A. J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0902232 · Cited by 172
Innate Immunity Mediates Follicular Transport of Particulate but Not Soluble Protein Antigen
Link, A., Zabel, F., Schnetzler, Y., Titz, A., Brombacher, F., & Bachmann, M. F. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103312 · Cited by 162
Phagocytosis of Apoptotic Cells by Macrophages From NOD Mice Is Reduced
O’Brien, B. A., Huang, Y., Geng, X., Dutz, J. P., & Finegood, D. T. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2481 · Cited by 162
Transposon-mediated BAC transgenesis in zebrafish and mice
Suster, M. L., Sumiyama, K., & Kawakami, K. (2009) · BMC Genomics · doi:10.1186/1471-2164-10-477 · Cited by 161
“Concatameric transgenes may be associated with silencing, instability, and genetic lesions both inside and around the transgenes [8,9] that seriously limit important experimental applications [10].”
Background
Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement
Bijl, M., Reefman, E., Horst, G., Limburg, P. C., & Kallenberg, C. G. M. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2005.035733 · Cited by 161
Retrotransposon-Induced Heterochromatin Spreading in the Mouse Revealed by Insertional Polymorphisms
Rebollo, R., Karimi, M. M., Bilenky, M., Gagnier, L., Miceli-Royer, K., Zhang, Y., Goyal, P., Keane, T., Jones, S. J. M., Hirst, M., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002301 · Cited by 165
“Some studies have found that only multiple tandem copies of a transgene (or even TEs) are able to induce heterochromatin but not a single copy [24–26].”
Background
Cutting Edge: Ectopic Expression of CD40 Ligand on B Cells Induces Lupus-Like Autoimmune Disease
Higuchi, T., Aiba, Y., Nomura, T., Matsuda, J., Mochida, K., Suzuki, M., Kikutani, H., Honjo, T., Nishioka, K., & Tsubata, T. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.1.9 · Cited by 160
Regulation of DNA methylation of Rasgrf1
Yoon, B. J., Herman, H., Sikora, A., Smith, L. T., Plass, C., & Soloway, P. D. (2001) · Nature Genetics · doi:10.1038/ng795 · Cited by 160
“The presence of transgene repeats has been correlated with changes in local DNA methylation and gene expression in diverse system”
Background
Regulation of Dendritic Cells and Macrophages by an Anti-Apoptotic Cell Natural Antibody that Suppresses TLR Responses and Inhibits Inflammatory Arthritis
Chen, Y., Khanna, S., Goodyear, C. S., Park, Y. B., Raz, E., Thiel, S., Grönwall, C., Vas, J., Boyle, D. L., Corr, M., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900948 · Cited by 158
The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis
Kemper, C., Mitchell, L. M., Zhang, L., & Hourcade, D. E. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801015105 · Cited by 165
Blebs and Apoptotic Bodies Are B Cell Autoantigens
Cocca, B. A., Cline, A. M., & Radic, M. Z. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.1.159 · Cited by 157
A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen
Xue, D., Shi, H., Smith, J. D. S., Chen, X., Noe, D. A., Cedervall, T., Yang, D. D., Eynon, E. E., Brash, D. E., Kashgarian, M. J., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0832411100 · Cited by 158
Transcriptional Silencing and Reactivation in Transgenic Zebrafish
Goll, M. G., Anderson, R. M., Stainier, D. Y. R., Spradling, A. C., & Halpern, M. E. (2009) · Genetics · doi:10.1534/genetics.109.102079 · Cited by 155
“Methylation occurs predominately at CpG dinucelotides in vertebrates, and tandem repeats are frequent targets of DNA methylation (Garrick et al. 1998).”
Background
Hepatitis C Virus Core Protein Inhibits Human T Lymphocyte Responses by a Complement-Dependent Regulatory Pathway
Yao, Z. Q., Nguyen, D. T., Hiotellis, A. I., & Hahn, Y. S. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5264 · Cited by 155
Simple piggyBac transposon-based mammalian cell expression system for inducible protein production
Li, Z., Michael, I. P., Zhou, D., Nagy, A., & Rini, J. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218620110 · Cited by 152
“In addition, transgenic fragments integrated in this way are often found to be inserted as concatemers, genomic structures that can be inactivated by “repeatinduced gene silencing” (6, 7).”
Background
A Polymorphism in the Complement ComponentC1qACorrelates with Prolonged Response Following Rituximab Therapy of Follicular Lymphoma
Racila, E. V., Link, B. K., Weng, W., Witzig, T. E., Ansell, S. M., Maurer, M. J., Huang, J., Dahle, C. E., Halwani, A. S., Levy, R., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0745 · Cited by 154
Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice
Li, J., Stein, T. D., & Johnson, J. A. (2004) · Physiological Genomics · doi:10.1152/physiolgenomics.00209.2003 · Cited by 154
Illegitimate DNA integration in mammalian cells
Würtele, H., Little, K. C., & Chartrand, P. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302074 · Cited by 152
Steroidogenic acute regulatory (StAR) protein: what's new?
Stocco, D. M. (1999) · BioEssays · doi:10.1002/(sici)1521-1878(199909)21:9 · Cited by 47
C1q Deficiency Leads to the Defective Suppression of IFN-α in Response to Nucleoprotein Containing Immune Complexes
Santer, D. M., Hall, B. E., George, T. C., Tangsombatvisit, S., Liu, C. L., Arkwright, P. D., & Elkon, K. B. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001731 · Cited by 151
Methylation dynamics of repetitive DNA elements in the mouse germ cell lineage
Lees‐Murdock, D. J., Felici, M. D., & Walsh, C. P. (2003) · Genomics · doi:10.1016/s0888-7543(03)00105-8 · Cited by 154
Sequences flanking the centromere of human chromosome 10 are a complex patchwork of arm-specific sequences, stable duplications and unstable sequences with homologies to telomeric and other centromeric locations
Jackson, M. S. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.2.205 · Cited by 150
Complement Activation Selectively Potentiates the Pathogenicity of the IgG2b and IgG3 Isotypes of a High Affinity Anti-Erythrocyte Autoantibody
da Silveira, S. A., Kikuchi, S., Fossati‐Jimack, L., Moll, T., Saito, T., Verbeek, J. S., Botto, M., Walport, M. J., Carroll, M. C., & Izui, S. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20012024 · Cited by 145
Episomal vectors for gene expression in mammalian cells
Van Craenenbroeck, K., Vanhoenacker, P., & Haegeman, G. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01645.x · Cited by 147
Transpostion of the Drosophila element mariner into the chicken germ line
Sherman, A., Dawson, A. J., Mather, C. M., Gilhooley, H. J., Li, Y., Mitchell, R., Finnegan, D., & Sang, H. (1998) · Nature Biotechnology · doi:10.1038/3497 · Cited by 147
“Expression of single copy transgenes may be less subject to downregulation than transgenes integrated in multicopy array”
Background
Murine CD93 (C1qRp) Contributes to the Removal of Apoptotic Cells In Vivo but Is Not Required for C1q-Mediated Enhancement of Phagocytosis
Norsworthy, P. J., Fossati‐Jimack, L., Cortés-Hernández, J., Taylor, P. R., Bygrave, A. E., Thompson, R. D., Nourshargh, S., Walport, M. J., & Botto, M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.6.3406 · Cited by 146
Macrophages from patients with SLE and rheumatoid arthritis have defective adhesion in vitro, while only SLE macrophages have impaired uptake of apoptotic cells
Tas, S. W., Quartier, P., Botto, M., & Fossati-Jimack, L. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2005.037143 · Cited by 144
Genetic Influences on the End-Stage Effector Phase of Arthritis
Ji, H., Gauguier, D., Ohmura, K., Gonzalez, A., Duchatelle, V., Danoy, P., Garchon, H., Degott, C., Lathrop, M. G., Benoist, C. O., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.3.321 · Cited by 144
Contemporary Transposon Tools: A Review and Guide through Mechanisms and Applications of Sleeping Beauty, piggyBac and Tol2 for Genome Engineering
Sandoval-Villegas, N., Nurieva, W., Amberger, M., & Ivics, Z. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105084 · Cited by 142
Local Amplification of Glucocorticoids by 11β-Hydroxysteroid Dehydrogenase Type 1 Promotes Macrophage Phagocytosis of Apoptotic Leukocytes
Gilmour, J. S., Coutinho, A. E., Cailhier, J., Man, T. Y., Clay, M. F., Thomas, G. D., Harris, H. J., Mullins, J. J., Seckl, J. R., Savill, J., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.12.7605 · Cited by 143
CD46 Plays a Key Role in Tailoring Innate Immune Recognition of Apoptotic and Necrotic Cells
Elward, K., Griffiths, M., Mizuno, M., Harris, C. L., Neal, J. W., Morgan, B. P., & Gasque, P. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506579200 · Cited by 147
Position-Dependent Methylation and Transcriptional Silencing of Transgenes in Inverted T-DNA Repeats: Implications for Posttranscriptional Silencing of Homologous Host Genes in Plants
Stam, M. E., Viterbo, A., Mol, J. N. M., & Kooter, J. M. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.11.6165 · Cited by 142
“With an IR locus that contains more T-DNAs, like the 21-1 IRcn locus, more interactions between the repeats are possible, which may result in a more highly condensed and silent state ( 21 , 79).”
Background
High concentrations of long interspersed nuclear element sequence distinguish monoallelically expressed genes
Allen, E., Horvath, S., Tong, F. K., Kraft, P. L., Spiteri, E., Riggs, A. D., & Marahrens, Y. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1737401100 · Cited by 141
Transgenic expression of the human A20 gene in cloned pigs provides protection against apoptotic and inflammatory stimuli
Oropeza, M., Petersen, B., Carnwath, J. W., Lucas‐Hahn, A., Lemme, E., Hassel, P., Herrmann, D., Barg‐Kues, B., Holler, S., Queisser, A., et al. (2009) · Xenotransplantation · doi:10.1111/j.1399-3089.2009.00556.x · Cited by 122
“High copy numbers of a construct inserted into a host genome can induce transgenic silencing by modifying the methylation pattern of the promoter [28].”
Background
Glucocorticoids Induce Protein S-Dependent Phagocytosis of Apoptotic Neutrophils by Human Macrophages
McColl, A., Bournazos, S., Franz, S., Perretti, M., Morgan, B. P., Haslett, C., & Dransfield, I. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803503 · Cited by 137
Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡
Paulk, N. K., Wursthorn, K., Wang, Z., Finegold, M. J., Kay, M. A., & Grompe, M. (2010) · Hepatology · doi:10.1002/hep.23481 · Cited by 135
Persistence of apoptotic cells without autoimmune disease or inflammation in CD14−/− mice
Devitt, A., Parker, K., Ogden, C. A., Oldreive, C., Clay, M., Melville, L. A., Bellamy, C. O. C., Lacy‐Hulbert, A., Gangloff, S. C., Goyert, S. M., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200410057 · Cited by 137
Methylation and colorectal cancer
Jubb, A. M., Bell, S. M., & Quirke, P. (2001) · The Journal of Pathology · doi:10.1002/path.923 · Cited by 134
“This links it to the maintenance of host defence and genomic integrity, but may compromise efforts at gene therapy [36].”
BackgroundInfluential
Requirements for Apoptotic Cell Contact in Regulation of Macrophage Responses
Lucas, M., Stuart, L. M., Zhang, A., Hodivala‐Dilke, K., Febbraio, M., Silverstein, R. L., Savill, J., & Lacy‐Hulbert, A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.4047 · Cited by 133
The Multiple Roles of the Innate Immune System in the Regulation of Apoptosis and Inflammation in the Brain
Griffiths, M., Gasque, P., & Neal, J. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181996688 · Cited by 130
Engineering the mouse genome by site-specific recombination
METZGER, D., & Feil, R. (1999) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(99)00012-9 · Cited by 128
DNA transposons in vertebrate functional genomics
Miskey, C., Izsvák, Z., Kawakami, K., & Ivics, Z. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4232-7 · Cited by 126
“Moreover, retroviral vectors have limited packaging size, and due to their long terminal repeats, they can induce gene silencing [50] and ectopic reporter gene expression.”
Background
Promoter methylation and transgene copy numbers predict unstable protein production in recombinant chinese hamster ovary cell lines
Osterlehner, A., Simmeth, S., & Göpfert, U. (2011) · Biotechnology and Bioengineering · doi:10.1002/bit.23216 · Cited by 131
Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context- dependent manner
Festenstein, R., Sharghi-Namini, S., Fox, M., Roderick, K., Tolaini, M., Norton, T., Saveliev, A., Kioussis, D., & Singh, P. B. (1999) · Nature Genetics · doi:10.1038/70579 · Cited by 123
“Although multiple transgene copies have been implicated in inducing variegatio”
Background
Chromatin and siRNA pathways cooperate to maintain DNA methylation of small transposable elements in Arabidopsis
Tran, R. K., Zilberman, D., de Bustos, C., Ditt, R. F., Henikoff, J. G., Lindroth, A. M., Delrow, J. J., Boyle, T., Kwong, S., Bryson, T. D., et al. (2005) · Genome biology · doi:10.1186/gb-2005-6-11-r90 · Cited by 124
“Small isolated elements might be more difficult to silence than large clustered elements [34-36], and mobile elements that are not silenced can damage the genome by replicative transposition [37].”
A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and Angelman syndromes
Gabriel, J. M., Merchant, M. A., Ohta, T., Ji, Y., Caldwell, R. G., Ramsey, M. J., Tucker, J. D., Longnecker, R., & Nicholls, R. D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.16.9258 · Cited by 122
Completion of the swine genome will simplify the production of swine as a large animal biomedical model
Walters, E. M., Wolf, E., Whyte, J. J., Mao, J., Renner, S., Nagashima, H., Kobayashi, E., Zhao, J., Wells, K. D., Critser, J. K., et al. (2012) · BMC Medical Genomics · doi:10.1186/1755-8794-5-55 · Cited by 121
“tially silence the transgene [93,94].”
Hypomorphic expression ofDkk1in thedoubleridgemouse: dose dependence and compensatory interactions withLrp6
MacDonald, B. T., Adamska, M., & Meisler, M. H. (2004) · Development · doi:10.1242/dev.01126 · Cited by 125
“In some cases, insertion of multiple transgene copies has been shown to induce DNA methylation and silencing of nearby genes (Garrick et al., 1998; McBurney et al., 2002).”
Background
Effects of Length and Location on the Cellular Response to Double-Stranded RNA
Wang, Q., & Carmichael, G. (2004) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.68.3.432-452.2004 · Cited by 124
Human C1qRp Is Identical with CD93 and the mNI-11 Antigen But Does Not Bind C1q
McGreal, E. P., Ikewaki, N., Akatsu, H., Morgan, B. P., & Gasque, P. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.10.5222 · Cited by 120
Cytosine methylation of repeated sequences in eukaryotes: the role of DNA pairing
Bender, J. (1998) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01225-0 · Cited by 120
A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development
Ashe, A., Morgan, D. K., Whitelaw, N. C., Bruxner, T. J., Vickaryous, N. K., Cox, L. L., Butterfield, N. C., Wicking, C., Blewitt, M. E., Wilkins, S. J., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-12-r182 · Cited by 117
“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].”
BackgroundSelf-citation
Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis
Hammond, J. W., Bellizzi, M. J., Ware, C., Qiu, W. Q., Saminathan, P., Li, H., Luo, S., Ma, S. A., Li, Y., & Gelbard, H. A. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.03.004 · Cited by 118
Cutting Edge: The Wiskott-Aldrich Syndrome Protein Is Required for Efficient Phagocytosis of Apoptotic Cells
Leverrier, Y., Lorenzi, R., Blundell, M. P., Brickell, P. M., Kinnon, C., Ridley, A. J., & Thrasher, A. J. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.4831 · Cited by 119
Transgenic Zebrafish as Sentinels for Aquatic Pollution
Carvan, M. J., Dalton, T. P., Stuart, G. W., & Nebert, D. W. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06875.x · Cited by 118
Modular Organization of the Carboxyl-Terminal, Globular Head Region of Human C1q A, B, and C Chains
Kishore, U., Gupta, S. K., Perdikoulis, M. V., Kojouharova, M. S., Urban, B. C., & Reid, K. B. M. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.2.812 · Cited by 118
Advances in the management of systemic lupus erythematosus
Morand, E. F., Fernandez‐Ruiz, R., Blazer, A., & Niewold, T. B. (2023) · BMJ · doi:10.1136/bmj-2022-073980 · Cited by 128
Reconstitution of the Complement Function in C1q-Deficient (C1qa−/−) Mice with Wild-Type Bone Marrow Cells
Petry, F., Botto, M., Holtappels, R., Walport, M. J., & Loos, M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.7.4033 · Cited by 117
Chromatin-Independent Binding of Serum Amyloid P Component to Apoptotic Cells
Familian, A., Zwart, B., Huisman, H. G., Rensink, I., Roem, D., Hordijk, P. L., Aarden, L. A., & Hack, C. E. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.2.647 · Cited by 117
Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)–mediated activation, and autoimmune disease
Wilkinson, R., Lyons, A. B., Roberts, D., Wong, M.-X., Bartley, P. A., & Jackson, D. E. (2002) · Blood · doi:10.1182/blood-2002-01-0027 · Cited by 116
Signaling through Up-Regulated C3a Receptor Is Key to the Development of Experimental Lupus Nephritis
Bao, L., Osawe, I., Haas, M., & Quigg, R. J. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.3.1947 · Cited by 115
The homeodomain protein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas
Hale, M. A., Kagami, H., Shi, L., Holland, A. M., Elsässer, H., Hammer, R. E., & MacDonald, R. J. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.07.026 · Cited by 115
Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens
Lech, M., Kulkarni, O. P., Pfeiffer, S., Savarese, E., Krug, A., Garlanda, C., Mantovani, A., & Anders, H. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072646 · Cited by 116
Recent advances in inducible gene expression systems.
Rossi, F., & Blau, H. (1998) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(98)80028-1 · Cited by 113
DNA Methylation, Epigenetics, and Evolution in Vertebrates: Facts and Challenges
Varriale, A. (2014) · International Journal of Evolutionary Biology · doi:10.1155/2014/475981 · Cited by 117
Impaired Opsonization with C3b and Phagocytosis ofStreptococcus pneumoniaein Sera from Subjects with Defects in the Classical Complement Pathway
Yuste, J., Sen, A. D., Truedsson, L., Jonsson, G. G., Tay, L. S., Hyams, C. J., Baxendale, H., Goldblatt, F., Botto, M., & Brown, J. (2008) · Infection and Immunity · doi:10.1128/iai.00291-08 · Cited by 109
Plasma proteome of severe acute respiratory syndrome analyzed by two-dimensional gel electrophoresis and mass spectrometry
Chen, J., Chang, Y., Yao, C., Chiueh, T., Huang, S., Chien, K.-Y., Chen, A., Chang, F., Wong, C., & Chen, Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407992101 · Cited by 108
Cd4+ T Cells from Lupus-Prone Mice Are Hyperresponsive to T Cell Receptor Engagement with Low and High Affinity Peptide Antigens
Vratsanos, G., Jung, S. S., Park, Y., & Craft, J. E. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.3.329 · Cited by 109
Genetic optimization of recombinant glycoprotein production by mammalian cells.
Fussenegger, M., Bailey, J. E., Hauser, H., & Mueller, P. P. (1999) · Trends in Biotechnology · doi:10.1016/s0167-7799(98)01248-7 · Cited by 113
The RING finger/B-Box factor TAM-1 and a retinoblastoma-like protein LIN-35 modulate context-dependent gene silencing in Caenorhabditis elegansPreprint
Hsieh, J., Liu, J., Kostas, S. A., Chang, C., Sternberg, P. W., & Fire, A. Z. (1999) · Genes & Development · doi:10.1101/gad.13.22.2958 · Cited by 109
“A potentially related class of silencing effects has been inferred from studies with transgenic fungi (Selker 1997), plants (Assaad et al. 1993; Ye and Signer 1996) and animals (Garrick et al. 1998).”
Background
Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications
Herzing, L. B. K. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.15.1707 · Cited by 109
Comparative Genomic and Transcriptomic Characterization of the Toxigenic Marine Dinoflagellate Alexandrium ostenfeldii
Jaeckisch, N., Yang, I., Wohlrab, S., Glöckner, G., Kroymann, J., Vogel, H., Cembella, A. D., & John, U. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028012 · Cited by 108
“[53]) and in mice [54], and heterochromatin formation was observed at these sites.”
Background
Identification of a Cytochrome P4502E1/Bid/C1q-dependent Axis Mediating Inflammation in Adipose Tissue after Chronic Ethanol Feeding to Mice
Sebastian, B. M., Roychowdhury, S., Tang, H., Hillian, A. D., Feldstein, A. E., Stahl, G. L., Takahashi, K., & Nagy, L. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.254201 · Cited by 107
Transgene Expression Is Associated with Copy Number and Cytomegalovirus Promoter Methylation in Transgenic Pigs
Kong, Q., Wu, M., Huan, Y., Zhang, L., Liu, H., Bou, G., Luo, Y., Mu, Y., & Liu, Z. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006679 · Cited by 106
“Generally, transgene copy number and DNA methylation status can influence transgene expression [13].”
Background
Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/ lpr Mice
Bao, L., Haas, M., Boackle, S. A., Kraus, D., Cunningham, P. N., Park, P., Alexander, J. J., Anderson, R. K., Culhane, K. K., Holers, V. M., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.7.3601 · Cited by 106
Nonphlogistic Clearance of Late Apoptotic Neutrophils by Macrophages: Efficient Phagocytosis Independent of β2 Integrins
Ren, Y., Stuart, L. M., Lindberg, F. P., Rosenkranz, A. R., Chen, Y., Mayadas, T. N., & Savill, J. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.7.4743 · Cited by 106

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Repeat-induced gene silencing in mammals

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks