The mouse H19 and Igf2 genes are oppositely imprinted and share enhancers that reside 3′ to the genes. The imprinted expression of these genes is coordinated by a 2-kb regulatory element, the differentially methylated domain (DMD), positioned between the two genes. The methylation status of this region determines the ability of the insulator factor CTCF to bind to its sites in the DMD. Deletions and mutations of the DMD that affect imprinting in the soma have little effect on the methylation pattern of H19 in the germline, suggesting that additional sequences and factors contribute to the earliest stages of imprinting regulation at this locus. Less is known about these initial steps, which include the marking of the parental alleles, the onset of allele-specific expression patterns and maintenance of the imprints in the preimplantation embryo. Here, we will focus on these early steps, summarizing what is known and what questions remain to be addressed.

1.
Ainscough JF, Dandolo L, Surani MA: Appropriate expression of the mouse H19 gene utilises three or more distinct enhancer regions spread over more than 130 kb. Mech Dev 91:365–368 (2000).
2.
Bartolomei MS, Zemel S, Tilghman SM: Parental imprinting of the mouse H19 gene. Nature 351:153–155 (1991).
3.
Barton SC, Arney KL, Shi W, Niveleau A, Fundele R, Surani MA, Haaf T: Genome-wide methylation patterns in normal and uniparental early mouse embryos. Hum Mol Genet 10:2983–2987 (2001).
4.
Bell AC, Felsenfeld G: Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485 (2000).
5.
Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W: Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417:945–948 (2002).
6.
Cox GF, Burger J, Lip V, Mau UA, Sperling K, Wu BL, Horsthemke B: Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 71:162–164 (2002).
7.
Davis TL, Trasler JM, Moss SB, Yang GJ, Bartolomei MS: Acquisition of the H19 methylation imprint occurs differentially on the parental alleles during spermatogenesis. Genomics 58:18–28 (1999).
8.
Davis TL, Yang GJ, McCarrey JR, Bartolomei MS: The H19 methylation imprint is erased and reestablished differentially on the parental alleles during male germ cell development. Hum Mol Genet 9:2885–2894 (2000).
9.
DeBaun MR, Niemitz EL, Feinberg AP: Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 72:156–160 (2003).
10.
DeChiara TM, Efstratiadis A, Robertson EJ: A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345:78–80 (1990).
11.
DeChiara TM, Robertson EJ, Efstratiadis A: Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64:849–859 (1991).
12.
Doherty AS, Mann MRW, Tremblay KD, Bartolomei MS, Schultz RM: Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 62:1526–1535 (2000).
13.
Drewell RA, Brenton JD, Ainscough JF, Barton SC, Hilton KJ, Arney KL, Dandolo L, Surani MA: Deletion of a silencer element disrupts H19 imprinting independently of a DNA methylation epigenetic switch. Development 127:3419–3428 (2000).
14.
Elson DA, Bartolomei MS: A 5′ differentially methylated sequence and the 3′ flanking region are necessary for H19 transgene imprinting. Mol Cell Biol 17:309–317 (1997).
15.
Engel N, Bartolomei MS: Mechanisms of insulator function in gene regulation and genomic imprinting. Int Rev Cytol 232:89–127 (2003).
16.
Engel NI, West AE, Felsenfeld G, Bartolomei MS: Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is revealed by CpG mutations. Nat Genet36:883–888 (2004).
17.
Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS: Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science 303:238–240 (2004).
18.
Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y: In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet 72:1338–1341 (2003).
19.
Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA: Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23 (2002).
20.
Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM: CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405:486–489 (2000).
21.
Humpherys D, Eggan K, Akutsu H, Hochedlinger K, Rideout WM 3rd, Biniszkiewicz D, Yanagimachi R, Jaenisch R: Epigenetic instability in ES cells and cloned mice. Science 293:95–97 (2001).
22.
Kaffer CR, Srivastava M, Park K-Y, Ives E, Hsieh S, Batle J, Grinberg A, Huang S-P, Pfeifer K: A transcriptional insulator at the imprinted H19/Igf2 locus. Genes Dev 14:1908–1919 (2000).
23.
Kanduri C, Pant V, Loukinov D, Pugacheva E, Qi CF, Wolffe A, Ohlsson R, Lobanenkov VV: Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol 10:853–856 (2000).
24.
Khosla S, Dean W, Brown D, Reik W, Feil R: Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod 64:918–926 (2001).
25.
Lee J, Inoue K, Ono R, Ogonuki N, Kohda T, Kaneko-Ishino T, Ogura A, Ishino F: Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129:1807–1817 (2002).
26.
Leighton PA, Saam JR, Ingram RS, Stewart CL, Tilghman SM: An enhancer deletion affects both H19 and Igf2 expression. Genes Dev 9:2079–2089 (1995).
27.
Li E, Beard C, Jaenisch R: Role for DNA methylation in genomic imprinting. Nature 366:362–365 (1993).
28.
Lucifero D, Mann MR, Bartolomei MS, Trasler JM: Gene-specific timing and epigenetic memory in oocyte imprinting. Hum Mol Genet 13:839–849 (2004).
29.
Maher ER, Brueton LA, Bowdin SC, Luharia A, Cooper W, Cole TR, Macdonald F, Sampson JR, Barratt CL, Reik W, Hawkins MM: Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet 40:62–64 (2003).
30.
Mann MRW, Chung YG, Nolen LD, Verona RI, Latham KE, Bartolomei MS: Disruption of imprinted gene methylation and expression in cloned preimplantation stage mouse embryos. Biol Reprod 69:902–914 (2003).
31.
Mann MR, Lee SS, Doherty AS, Verona RI, Nolen LD, Schultz RM, Bartolomei MS: Selective loss of imprinting in the placenta following preimplantation development in culture. Development 131:3727–3735 (2004).
32.
Mayer W, Niveleau A, Walter J, Fundele R, Haaf T: Demethylation of the zygotic paternal genome. Nature 403:501–502 (2000).
33.
Niemitz EL, Feinberg AP: Epigenetics and assisted reproductive technology: a call for investigation. Am J Hum Genet 74:599–609 (2004).
34.
Obata Y, Kono T: Maternal primary imprinting is established at a specific time for each gene throughout oocyte growth. J Biol Chem 277:5285–5289 (2002).
35.
Ohlsson R, Renkawitz R, Lobanenkov V: CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet 17:520–527 (2001).
36.
Olek A, Walter J: The pre-implantation ontogeny of the H19 methylation imprint. Nat Genet 17:275–276 (1997).
37.
Orstavik KH, Eiklid K, van der Hagen CB, Spetalen S, Kierulf K, Skjeldal O, Buiting K: Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am J Hum Genet 72:218–219 (2003).
38.
Oswald J, Engemann S, Lane N, Mayer W, Olek A, Fundele R, Dean W, Reik W, Walter J: Active demethylation of the paternal genome in the mouse zygote. Curr Biol 10:475–478 (2000).
39.
Pant V, Mariano P, Kanduri C, Mattsson A, Lobanenkov V, Heuchel R, Ohlsson R: The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains. Genes Dev 17:586–590 (2003).
40.
Rougier N, Bourc’his D, Gomes DM, Niveleau A, Plachot M, Páldi A, Viegas-Péquignot, E: Chromosome methylation patterns during mammalian preimplantation development. Genes Dev 12:2108–2113 (1998).
41.
Santos F, Hendrich B, Reik W, Dean W: Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 241:172–182 (2002).
42.
Schoenherr CJ, Levorse JM, Tilghman SM: CTCF maintains differential methylation at the Igf2/H19 locus. Nat Genet 33:66–69 (2003).
43.
Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A: Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet 36:958–960 (2004).
44.
Szabo PE, Tang S-H, Rentsendorj A, Pfeifer GP, Mann JR: Maternal-specific footprints at putative CTCF sites in the H19 imprinting control region give evidence for insulator function. Curr Biol 10:607–610 (2000).
45.
Szabo PE, Tang SH, Silva FJ, Tsark WM, Mann JR: Role of CTCF binding sites in the Igf2/H19 imprinting control region. Mol Cell Biol 24:4791–4800 (2004).
46.
Thorvaldsen JL, Duran KL, Bartolomei MS: Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev 12:3693–3702 (1998).
47.
Thorvaldsen JL, Mann MR, Nwoko O, Duran KL, Bartolomei MS: Analysis of sequence upstream of the endogenous H19 gene reveals elements both essential and dispensable for imprinting. Mol Cell Biol 22:2450–2462 (2002).
48.
Tremblay KD, Saam JR, Ingram RS, Tilghman SM, Bartolomei MS: A paternal-specific methylation imprint marks the alleles of the mouse H19 gene. Nat Genet 9:407–413 (1995).
49.
Tremblay KD, Duran KL, Bartolomei MS: A 5′ 2-kilobase-pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development. Mol Cell Biol 17:4322–4329 (1997).
50.
Ueda T, Abe K, Miura A, Yuzuriha M, Zubair M, Noguchi M, Niwa K, Kawase Y, Kona T, Matsuda Y, Fujimoto H, Shibata H, Hayashizaki Y, Sasaki H: The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development. Genes Cells 5:649–659 (2000).
51.
West AG, Fraser P: Remote control of gene transcription. Hum Mol Genet 14 Spec No 1:R101–R111 (2005).
52.
Yamazaki Y, Mann MR, Lee SS, Marh J, McCarrey JR, Yanagimachi R, Bartolomei MS: Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci USA 100:12207–12212 (2003).
53.
Yoo-Warren H, Pachnis V, Ingram RS, Tilghman SM: Two regulatory domains flank the mouse H19 gene. Mol Cell Biol 8:4707–4715 (1988).
54.
Zemel S, Bartolomei MS, Tilghman SM: Physical linkage of two mammalian imprinted genes. Nat Genet 2:61–65 (1992).
© 2006 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.