Sensitive Flow Cytometric Analysis Reveals a Novel Type of Parent-of-Origin Effect in the Mouse Genome
Open accessAbstract
The discovery of classic parental imprinting came, at least in part, from the analysis of transgene expression in mice. It was noticed that some transgenes were only expressed following paternal transmission and that others sometimes showed differential patterns of methylation depending on the parent of origin. Here, we present evidence of a novel and more subtle form of parental imprinting by taking advantage of the highly sensitive detection of murine transgene expression afforded by flow cytometry. We have produced nine lines of transgenic mice carrying a GFP reporter linked to the human alpha-globin promoter and enhancer elements, which direct expression to erythroid cells. A high proportion of transgenic lines, four of the nine, display significantly lower levels of expression following maternal transmission. Both the percentage of expressing cells and the mean fluorescence in expressing cells are between 10% and 30% lower following maternal transmission. These effects are reversible upon passage through the opposite germline. This finding raises the possibility that differences in the epigenetic state of the maternal and paternal chromosomes in adult somatic cells are more widespread than was previously thought.
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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 [14]
Cites
Epigenetic inheritance at the agouti locus in the mouse
Morgan, H. D., Sutherland, H. G. E., Martin, D. I. K., & Whitelaw, E. (1999) · Nature Genetics · doi:10.1038/15490 · Cited by 1,476 · see citing works
Self-citationRakyan, V. K., Chong, S., Blewitt, M. E., Cuthbert, P. C., Morgan, H. D., Luu, K. V. K., & Whitelaw, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0436776100 · Cited by 642 · see citing works
Self-citationMetastable epialleles in mammals
Rakyan, V. K., Blewitt, M. E., Druker, R., Preis, J. I., & Whitelaw, E. (2002) · Trends in Genetics · doi:10.1016/s0168-9525(02)02709-9 · Cited by 499 · see citing works
Self-citationGenomic imprinting determines methylation of parental alleles in transgenic mice
Reik, W., Collick, A., Norris, M., Barton, S., & Surani, M. (1987) · Nature · doi:10.1038/328248a0 · Cited by 486 · see citing works
Degree of methylation of transgenes is dependent on gamete of origin
Sapienza, C., Peterson, A., Rossant, J., & Balling, R. (1987) · Nature · doi:10.1038/328251a0 · Cited by 391 · see citing works
HUMAN TYPE 1 DIABETES AND THE INSULIN GENE: Principles of Mapping Polygenes
Bennett, S. T., & Todd, J. A. (1996) · Annual Review of Genetics · doi:10.1146/annurev.genet.30.1.343 · Cited by 287 · see citing works
Epigenetic control of transgene expression and imprinting by genotype-specific modifiers
Allen, N. D., Norris, M. L., & Surani, M. A. (1990) · Cell · doi:10.1016/0092-8674(90)90195-k · Cited by 235 · see citing works
Hadchouel, M., Farza, H., Simon, D., Tiollais, P., & Pourcel, C. (1987) · Nature · doi:10.1038/329454a0 · Cited by 194 · see citing works
The vagaries of variegating transgenes
Martin, D. I. K., & Whitelaw, E. (1996) · BioEssays · doi:10.1002/bies.950181111 · Cited by 160 · see citing works
Self-citationPosition-dependent variegation of globin transgene expression in mice.
Robertson, G., Garrick, D., Wu, W. W., Kearns, M., Martin, D. I. K., & Whitelaw, E. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5371 · Cited by 159 · see citing works
Self-citationAnderson, M. T., Tjioe, I., Lorincz, M. C., Parks, D. R., Herzenberg, L. A., Nolan, G. P., & Herzenberg, L. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8508 · Cited by 105 · see citing works
Age-dependent silencing of globin transgenes in the mouse
Robertson, G. (1996) · Nucleic Acids Research · doi:10.1093/nar/24.8.1465 · Cited by 93 · see citing works
Parental Imprinting in Drosophila
Lloyd, V. K. (2000) · Genetica · doi:10.1023/a:1026592318341 · Cited by 84 · see citing works
Natural selection and the function of genome imprinting: beyond the silenced minority
de Villena, F. P., de la Casa‐Esperón, E., & Sapienza, C. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(00)02134-x · Cited by 82 · see citing works
A Globin Enhancer Acts by Increasing the Proportion of Erythrocytes Expressing a Linked Transgene
Sutherland, H. G. E., Martin, D. I. K., & Whitelaw, E. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.3.1607 · Cited by 75 · see citing works
Self-citationKlutz, M., Brockmann, D., & Lohmann, D. R. (2002) · The American Journal of Human Genetics · doi:10.1086/341284 · Cited by 71 · see citing works
Analysis of the human alpha-globin gene cluster in transgenic mice.
Sharpe, J. A., Wells, D. J., Whitelaw, E., Vyas, P., Higgs, D. R., & Wood, W. G. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.23.11262 · Cited by 65 · see citing works
Self-citationRegulation of genomic imprinting by gametic and embryonic processes.Preprint
Chaillet, J. R., Bader, D., & Leder, P. (1995) · Genes & Development · doi:10.1101/gad.9.10.1177 · Cited by 65 · see citing works
The Y Chromosome of Drosophila melanogaster Exhibits Chromosome-Wide Imprinting
Maggert, K. A., & Golic, K. G. (2002) · Genetics · doi:10.1093/genetics/162.3.1245 · Cited by 54 · see citing works
Garrick, D., Sutherland, H. G. E., Robertson, G., & Whitelaw, E. (1996) · Nucleic Acids Research · doi:10.1093/nar/24.24.4902 · Cited by 48 · see citing works
Self-citationComplex 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 · see citing works
Genomic imprinting: Lessons from mouse transgenes
Chaillet, J. R. (1994) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(94)90255-0 · Cited by 44 · see citing works
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Molecular studies of major depressive disorder: the epigenetic perspective
Mill, J. S., & Petronis, A. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001992 · Cited by 302 · see citing works
An <i>N</i> -ethyl- <i>N</i> -nitrosourea screen for genes involved in variegation in the mouse
Blewitt, M. E., Vickaryous, N. K., Hemley, S. J., Ashe, A., Bruxner, T. J., Preis, J. I., Arkell, R., & Whitelaw, E. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409375102 · Cited by 186 · see citing works
Self-citationAshe, 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 · see citing works
Self-citationMould, A. W., Pang, Z., Pakusch, M., Tonks, I. D., Stark, M. S., Carrie, D., Mukhopadhyay, P., Seidel, A., Ellis, J. J., Deakin, J. E., et al. (2013) · Epigenetics & Chromatin · doi:10.1186/1756-8935-6-19 · Cited by 100 · see citing works
Developmental Consequences of Sexual Dimorphism During Pre‐implantation Embryonic Development
Gutiérrez‐Adán, A., Perez‐Crespo, M., Fernández‐González, R., Ramirez, M., Moreira, P., Pintado, B., Lonergan, P., & Rizos, D. V. (2006) · Reproduction in Domestic Animals · doi:10.1111/j.1439-0531.2006.00769.x · Cited by 97 · see citing works
The Use of Mouse Models to Study EpigeneticsPreprint
Blewitt, M., & Whitelaw, E. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a017939 · Cited by 73 · see citing works
Self-citationPosition effect variegation and imprinting of transgenes in lymphocytes
Williams, A., Harker, N., Ktistaki, E., Veiga‐Fernandes, H., Roderick, K., Tolaini, M., Norton, T., Williams, K., & Kioussis, D. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn085 · Cited by 57 · see citing works
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 · see citing works
Gladyshev, E. A., & Kleckner, N. E. (2017) · Nature Genetics · doi:10.1038/ng.3857 · Cited by 45 · see citing works
The first mouse mutants of D14Abb1e (Fam208a) show that it is critical for early development
Harten, S. K., Bruxner, T. J. C., Bharti, V., Blewitt, M. E., Nguyen, T.-M.-T., Whitelaw, E., & Epp, T. A. (2014) · Mammalian Genome · doi:10.1007/s00335-014-9516-0 · Cited by 45 · see citing works
Self-citationPapathanasiou, P., & Goodnow, C. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095817 · Cited by 42 · see citing works
藤木, 豊., Tao, K. X., Bianchi, D. W., Giel–Moloney, M., Leiter, A. B., & Johnson, K. L. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20533 · Cited by 40 · see citing works
Imprinting Capacity of Gamete Lineages in Caenorhabditis elegans
Sha, K., & Fire, A. Z. (2005) · Genetics · doi:10.1534/genetics.104.040303 · Cited by 30 · see citing works
Blewitt, M. E., Chong, S., & Whitelaw, E. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.08.011 · Cited by 24 · see citing works
Self-citationdel Fierro, A. T., den Hamer, B., Benetti, N., Jansz, N., Chen, K., Beck, T. J., Vanyai, H. K., Gurzau, A. D., Daxinger, L., Xue, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40992-6 · Cited by 26 · see citing works
McCann, J. A., Xu, Y., Fréchette, R., Guazzarotti, L., & Polychronakos, C. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0553 · Cited by 25 · see citing works
Youngson, N. A., Vickaryous, N. K., van der Horst, A., Epp, T. A., Harten, S. K., Fleming, J. S., Khanna, K. K., de Kretser, D. M., & Whitelaw, E. (2011) · Mammalian Genome · doi:10.1007/s00335-011-9317-7 · Cited by 25 · see citing works
Self-citationFraser, S. T., Isern, J., & Baron, M. H. (2010) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(10)76022-5 · Cited by 20 · see citing works
Harten, S. K., Oey, H., Bourke, L. M., Bharti, V., Isbel, L., Daxinger, L., Faou, P., Robertson, N. O., Matthews, J. M., & Whitelaw, E. (2015) · BMC Biology · doi:10.1186/s12915-015-0128-2 · Cited by 19 · see citing works
Self-citationEpigenetics and Chronic Diseases: An Overview
Smith, R. G., & Mill, J. (2011) · Springer eBooks · doi:10.1007/978-1-84882-644-1_1 · Cited by 13 · see citing works
Funnell, A. P. W., Vernimmen, D., Lim, W. F., Mak, K. S., Wienert, B., Martyn, G. E., Artuz, C. M., Burdach, J., Quinlan, K. G. R., Higgs, D. R., et al. (2014) · BMC Molecular Biology · doi:10.1186/1471-2199-15-8 · Cited by 13 · see citing works
Self-citationSorolla, A., Tallack, M. R., Oey, H., Harten, S. K., Daxinger, L., Magor, G. W., Combes, A. N., Ilsley, M. D., Whitelaw, E., & Perkins, A. C. (2014) · Genomics · doi:10.1016/j.ygeno.2014.09.013 · Cited by 13 · see citing works
Self-citationNo evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations
Youngson, N. A., Epp, T. A., Roberts, A. R., Daxinger, L., Ashe, A., Huang, E., Lester, K. L., Harten, S. K., Kay, G. F., Cox, T. C., et al. (2013) · Mammalian Genome · doi:10.1007/s00335-013-9451-5 · Cited by 13 · see citing works
Self-citationStrain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers
Elmer, J. L., & Ferguson‐Smith, A. C. (2020) · Viruses · doi:10.3390/v12080810 · Cited by 12 · see citing works
The Relevance of Epigenetics to Major Psychosis
Mill, J. S., & Petronis, A. (2008) · Springer eBooks · doi:10.1007/978-1-4020-9187-2_23 · Cited by 7 · see citing works
The Rainbow of Fluorescent Proteins
Galbraith, D. W. (2004) · Methods in cell biology · doi:10.1016/s0091-679x(04)75006-2 · Cited by 7 · see citing works
Nonmammalian Parent-of-Origin Effects
de la Casa‐Esperón, E. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-011-3_19 · Cited by 6 · see citing works
Hu, P., Hao, Y., Tang, W. H., Diering, G. H., Zou, F., & Kafri, T. (2025) · Viruses · doi:10.3390/v17020276 · Cited by 5 · see citing works
Roberts, A. R., Huang, E., Jones, L., Daxinger, L., Chong, S., & Whitelaw, E. (2013) · Chromosoma · doi:10.1007/s00412-013-0427-8 · Cited by 5 · see citing works
Self-citationRelative transgene expression frequencies in homozygous versus hemizygous transgenic mice
Chang, S.-P., Opsahl, M. L., Whitelaw, B., Morley, S. D., & West, J. D. (2013) · Transgenic Research · doi:10.1007/s11248-013-9732-5 · Cited by 5 · see citing works
Towards the molecular mechanisms of transgenerational epigenetic inheritance
Freeman, D. M., & Wang, Z. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816363-4.00007-9 · Cited by 4 · see citing works
Sorolla, M. A., Marqués, M., Parisi, E., & Sorolla, A. (2021) · Animals · doi:10.3390/ani11072103 · Cited by 3 · see citing works
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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 · see citing works
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Choi, K. (2024) · KAIST research series · doi:10.1007/978-981-97-0830-7_11 · Cited by 1 · see citing works
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Blewitt, M. E., & Whitelaw, E. (2005) · Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics · doi:10.1002/047001153x.g103324
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Ashe, A., & Hawes, J. J. (2026) · Frontiers in Epigenetics and Epigenomics · doi:10.3389/freae.2025.1733711
- Authors
- Preis, J. I., Downes, M., Oates, N. A., Rasko, J. E. J., & Whitelaw, E.
- Affiliations
- The University of Sydney (AU)
- Centenary Institute (AU)
- Corresponding author
- Whitelaw, Emma
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 13
- Issue
- 11
- Pages
- 955-959
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2023085607
- Cited by
- 36
- References
- 22
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2017: 1 · 2015: 1 · 2014: 3 · 2013: 5 · 2012: 1
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- genomic imprinting, parent-of-origin effects, transgenic mice, GFP reporter, erythroid cells, transgene expression, DNA methylation, epigenetic inheritance, mother-to-child transmission, paternal transmission
- MeSH terms
- Animals, Cell Separation, Flow Cytometry, Luminescent Proteins, Mice, Transgenic, Pedigree, Sensitivity and Specificity, Genome, Genes, Reporter, Genomic Imprinting, Transgenes, Green Fluorescent Proteins, Mice
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