Abstract
Genomic imprinting is the process in mammals by which gamete-specific epigenetic modifications establish the differential expression of the two alleles of a gene. The tightly linked H19 and Igf2 genes are expressed in tissues of endodermal and mesodermal origin, with H19 expressed from the maternal chromosome and Igf2 expressed from the paternal chromosome. A model has been proposed to explain the reciprocal imprinting of these genes1; in this model, expression of the genes is governed by competition between their promoters for a common set of enhancers. An extra set of enhancers might be predicted to relieve the competition, thereby eliminating imprinting. Here we tested this prediction by generating mice with a duplication of the endoderm-specific enhancers. The normally silent Igf2 gene on the maternal chromosome was expressed in liver, consistent with relief from competition. We then generated a maternal chromosome containing a single set of enhancers located equidistant from Igf2 and H19; the direction of the imprint was reversed. Thus, the location of the enhancers determines the outcome of competition in liver, and the strength of the H19 promoter is not sufficient to silence Igf2.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bartolomei, M. S. & Tilghman, S. M. Parental imprinting of mouse chromosome 7. Semin. Dev. Biol. 3, 107–117 (1992).
Yoo-Warren, H., Pachnis, V., Ingram, R. S. & Tilghman, S. M. Two regulatory domains flank the mouse H19 gene. Mol. Cell. Biol. 8, 4707–4715 (1988).
Leighton, P. A., Saam, J. R., Ingram, R. S., Stewart, C. L. & Tilghman, S. M. An enhancer deletion affects both H19 and Igf2 expression. Genes Dev. 9, 2079–2089 (1995).
Bartolomei, M. S., Webber, A. L., Brunkow, M. E. & Tilghman, S. M. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 7, 1663–1673 (1993).
Ferguson-Smith, A. C., Sasaki, H., Cattanach, B. M. & Surani, M. A. Parental-origin-specific epigenetic modifications of the mouse H19 gene. Nature 362, 751–755 (1993).
Li, E., Beard, C. & Jaenisch, R. The role of DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).
Choi, O.-R. B. & Engel, J. D. Developmental regulation of β-globin switching. Cell 55, 17–26 (1988).
Nickol, J. M. & Felsenfeld, G. Bidirectional control of the chicken β- and ε-globin genes by a shared enhancer. Proc. Natl Acad. Sci. USA 85, 2548–2552 (1988).
Gu, H., Zou, Y.-R. & Rajewsky, K. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73, 1155–1164 (1993).
Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A. & Tilghman, S. M. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 375, 34–39 (1995).
Brunkow, M. E. & Tilghman, S. M. Ectopic expression of the H19 gene in mice causes prenatal lethality. Genes Dev. 5, 1092–1101 (1991).
Sasaki, H. et al. Parental imprinting: potentially active chromatin of the repressed maternal allele of the mouse insulin-like growth factor (Igf2) gene. Genes Dev. 6, 1843–1856 (1992).
Feil, R., Walter, J., Allen, N. D. & Reik, W. Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes. Development 120, 2933–2943 (1994).
Brandeis, M. et al. The ontogeny of allele-specific methylation associated with imprinted genes in the mouse. EMBO J. 12, 3669–3677 (1993).
Walter, J. et al. in Epigenetic Mechanisms of Gene Regulation(eds Russo, V. E. A., Martienssen, R. A. & Riggs, A. D.) 195–213 (Cold Spring Harbor Laboratory Press, (1996)).
Kellum, R. & Schedl, P. Aposition-effect assay for boundaries of higher order chromosomal domains. Cell 64, 941–950 (1991).
Kellum, R. & Schedl, P. Agroup of scs elements function as domain boundaries in an enhancer-blocking assay. Mol. Cell Biol. 12, 2424–2431 (1992).
Ripoche, M.-A., Kress, C., Poirier, F. & Dandolo, L. Deletion of the H19 transcription unit reveals the existence of a putative imprinting control element. Genes Dev. 11, 1596–1604 (1997).
Lyko, F., Brenton, J. D., Surani, M. A. & Paro, R. An imprinting element from the mouse H19 locus functions as a silencer in Drosophila. Nature Genet. 16, 171–173 (1997).
McCarrick, J. W. II, Parnes, J. R., Seong, R. H., Solter, D. & Knowles, B. B. Positive-negative selection gene targeting with the diphtheria toxin A-chain gene in mouse embryonic stem cells. Transgen. Res. 2, 183–190 (1993).
Johnson, K. A. et al. Transgenic mice for the preparation of hygromycin-resistant primary embryonic fibroblast feeder layers for embryonic stem cell selections. Nucleic Acids Res. 23, 1273–1275 (1995).
Ramirez-Solis, R. et al. Genomic DNA microextraction: a method to screen numerous samples. Anal. Biochem. 201, 331–335 (1992).
Feinberg, A. P. & Vogelstein, B. Atechnique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 137, 266–267 (1984).
Chu, G., Vollrath, D. & Davis, R. W. Separation of large DNA molecules by contour-clamped homogenous electric fields. Science 234, 1582–1585 (1986).
Sauer, B. & Henderson, N. Targeted insertion of exogenous DNA into the eukaryotic genome by the re recombinase. New Biol. 2, 441–449 (1990).
Auffray, C. & Rougeon, F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur. J. Biochem. 107, 303–314 (1980).
Bartolomei, M. S., Zemel, S. & Tilghman, S. M. Parental imprinting of the mouse H19 gene. Nature 351, 153–155 (1991).
Dudov, K. P. & Perry, R. P. The gene encoding the mouse ribosomal protein L32 contains a uniquely expressed intron containing gene and an unmutated processed gene. Cell 37, 457–468 (1984).
Acknowledgements
We thank T. Watanabe and S. Wang for help in generating chimaeras and the members of our laboratory for discussions. This work was supported by a grant from the National Institute of General Medical Science. S.M.T. is an Investigator of the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Webber, A., Ingram, R., Levorse, J. et al. Location of enhancers is essential for the imprinting of H19 and Igf2 genes. Nature 391, 711–715 (1998). https://doi.org/10.1038/35655
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/35655
This article is cited by
-
CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains
Genome Biology (2019)
-
Birth of fertile bimaternal offspring following intracytoplasmic injection of parthenogenetic haploid embryonic stem cells
Cell Research (2016)
-
The long noncoding RNA RNCR2 directs mouse retinal cell specification
BMC Developmental Biology (2010)
-
Statistical significance of cis-regulatory modules
BMC Bioinformatics (2007)
-
The human and mouse H19 imprinting control regions harbor an evolutionarily conserved silencer element that functions on transgenes in Drosophila
Development Genes and Evolution (2006)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.