Genomic Imprinting at the Transcriptional Level

Abstract

Genomic imprinting is an epigenetic mechanism of gene regulation that causes genes to be expressed from only one of the two parentally inherited chromosomes in mammals. This form of regulation affects less than 1% of genes and has crucial roles in embryonic growth, development and brain function. Imprinted genes are often clustered in large chromosomal domains and their expression is regulated by cis‐acting imprinting control regions (ICRs). ICRs carry a methylation imprint that is laid down in one of the two parental germlines, when the two genomes are separated, to distinguish the paternal and the maternal alleles. To date, regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers or cis‐regulation induced by long noncoding RNAs (ncRNAs). Aberrant expression of imprinted genes leads to human pathologies and is frequent in cancer. Genomic imprinting provides a unique model for studying the epigenetic influence on transcriptional activity and repression.

Key Concepts:

  • A subset of genes in the mammalian genome (less than 1%) known as imprinted genes are expressed exclusively from one of the two parental alelles.

  • The existence of genomic imprinting highlights the nonequivalence of parental genomes and precludes the viability of mammalian embryos with exclusive contribution of genetic material from one of the parents.

  • Imprinted genes are involved in fetal growth and placental development in the uterus, as well as brain function and metabolism in adults.

  • Genomic imprinting has been reported in placental mammals and marsupials but not in montremes.

  • Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are co‐ordinatively regulated.

  • Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alelles during gametogenesis.

  • DNA methylation is the bona fide imprint mark that distinguishes the two parental alleles at the ICRs, resisting the wave of DNA demethylation after fertilisation and being erased and reset in the germline.

  • Insulation of common enhancers by the methylated sensitive protein CTCF explains the imprinting regulation at the Igf2/H19 region.

  • Silencing of genes in cis by long non‐coding RNAs explains the imprinting regulation for at least three imprinted clusters by yet unknown mechanisms.

  • Deregulation of genomic imprinting can cause imprinted disorders in humans which exhibit parent of origin effects in their pattern of inheritance.

Keywords: genomic imprinting; epigenetics; DNA methylation; histone modifications; noncoding RNAs (ncRNAs)

Figure 1.

Genomic imprinting and non‐Mendelian inheritance. Diploid somatic cells contain maternally inherited chromosomes (red) and paternally inherited chromosomes (blue). Most of the genes on these chromosomes are potentially biallelically expressed (box C). Some of these chromosomes have imprinted genes expressed from the maternally inherited allele (box B) and repressed on the other homologue, and imprinted genes expressed from the paternally inherited allele (box A). Expressed alleles are shown in green and repressed alleles in red. Mutations at imprinted genes have different outcomes according to the parental chromosome from which the mutation was inherited: a mutation (yellow star) in an imprinted gene will only result in phenotypic consequences if the mutation is transmitted on the active allele, in the case depicted, the paternal chromosome.

Figure 2.

The life cycle of the methylation imprint. The scheme illustrates the key stages of genomic imprinting during germ cell and embryonic development (only two homologous chromosomes are shown); in blue letters, genomic wide reprogramming events in terms of DNA methylation are shown. Erasure of imprints: The imprint inherited from the previous generation is erased on both parental chromosomes during germ cell development (‘erased’ chromosomes are shown in white). During erasure, there is a genome‐wide demethylation in the germ cells, which in the mouse is completed by embryonic days 12–13 in both sexes. All methylation imprints are probably erased at this stage. Establishment of imprints: New imprints are established according to the sex of the germ line for the next generation (DNA methylated ICR is marked in black, male chromosomes in blue and female chromosomes in red). The acquisition of methylation imprints seems to occur by de novo methylation during oocyte growth and before meiosis during spermatogenesis. DNMT3A and DNMT3L have been implicated in the establishment of all maternal imprints, KDM1B in some, and transcription across the ICR occurs in most of the ICRs. Transcription is important for the establishment of the methylation for at least one ICR. DNMT3A is also essential to establish methylation imprints in the male germline and DNMT3L is important for only one paternal ICR. Maintenance of imprints: Once the methylation differences between alleles are established, they need to be maintained after fertilisation. They are protected from the genome‐wide wave of demethylation observed during pre‐implantation development. This depends on the residual DNMT1, the maintenance DNA methyltransferase and in the proteins PGC7/STELLA and ZFP57; around the time of implantation, a wave of de novo methylation occurs. The unmethylated ICR is protected from the gain of methylation. At this stage, additional differential methylated regions are established at imprinted clusters, the so‐called secondary DMRs. Reading: Although not part of the developmental cycle of imprinting, the maternal and paternal imprints are translated into monoallelic expression (indicated by arrows) during development. ICRs regulate the epigenotype of neighbouring imprinted genes in cis and are indicated as paternal ICR and maternal ICR (adapted from Reik and Walter, ).

Figure 3.

Models of imprinting regulation in clusters. (a) The insulator model: regulation of imprinting at the Igf2/H19 locus on mouse distal chromosome 7. H19 encodes a ncRNA expressed from the maternal allele only; H19 shares enhancers at the 3′ end with the paternally expressed gene Igf2; Ins2 gene is imprinted in the yolk sac, expressed from the paternal allele. On the maternal chromosome, the unmethylated ICR is bound by the insulator factor CTCF, preventing the downstream enhancers to reach Igf2 gene and allowing H19 to be expressed; on the paternal chromosome, CTCF can not bind to the methylated ICR allowing the enhancers to reach Igf2 promoter and express the gene; methylation of the ICR might spread to the nearby H19 gene and renders H19 inactive. Looping structures are formed as a consequence of the boundary formed by CTCF and perhaps other factors. (b) The ncRNA model: Regulation of imprinting at the Igf2r locus on mouse proximal chromosome 17. The Igf2r cluster contains three maternally expressed genes (Igf2r and the placental imprinted genes, Slc22a2 and Slc22a3), a paternally expressed ncRNA (Airn) and three putative nonimprinted genes (Mas1, Slc22a1 and Pgl). The ICR is present in methylated on the maternal chromosome. The unmethylated ICR on the paternal chromosome serves as an active promoter for the Airn gene that is responsible for the inactivation in cis of Igf2r, Slc22a2 and Slc22a3. The mechanism through which Airn ncRNA mediates silencing is unknown but might involve the formation of a silent compartment and the recruitment of protein repressive complexes.

close

References

Barlow DP, Stoger R, Herrmann BG, Saito K and Schweifer N (1991) The mouse insulin‐like growth factor type‐2 receptor is imprinted and closely linked to the Tme locus. Nature 349: 84–87.

Bartolomei MS (2009) Genomic imprinting: employing and avoiding epigenetic processes. Genes & Development 23: 2124–2133.

Bartolomei MS, Zemel S and Tilghman SM (1991) Parental imprinting of the mouse H19 gene. Nature 351: 153–155.

Bourc'his D, Xu GL, Lin CS, Bollman B and Bestor TH (2001) Dnmt3L and the establishment of maternal genomic imprints. Science 294: 2536–2539.

Brideau CM, Kauppinen KP, Holmes R and Soloway PD (2010) A non‐coding RNA within the Rasgrf1 locus in mouse is imprinted and regulated by its homologous chromosome in trans. PLoS One 5: e13784.

Cattanach BM and Beechey CV (1990) Autosomal and X‐chromosome imprinting. Development 108: 63–72.

Charalambous M, da Rocha ST and Ferguson‐Smith AC (2007) Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life. Current Opinion in Endocrinology, Diabetes and Obesity 14: 3–12.

Chaumeil J, Le Baccon P, Wutz A and Heard E (2006) A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes & Development 20: 2223–2237.

Chotalia M, Smallwood SA, Ruf N et al. (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes & Development 23: 105–117.

Ciccone DN, Su H, Hevi S et al. (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461: 415–418.

Cui H, Cruz‐Correa M, Giardiello FM et al. (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299: 1753–1755.

DeChiara TM, Robertson EJ and Efstratiadis A (1991) Parental imprinting of the mouse insulin‐like growth factor II gene. Cell 64: 849–859.

Demars J, Rossignol S, Netchine I et al. (2011) New insights into the pathogenesis of Beckwith–Wiedemann and Silver–Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects. Human Mutation 32(10): 1171–1182.

Edwards CA, Mungall AJ, Matthews L et al. (2008) The evolution of the DLK1‐DIO3 imprinted domain in mammals. PLoS Biology 6: e135.

Ferguson‐Smith AC, Cattanach BM, Barton SC, Beechey CV and Surani MA (1991) Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature 351: 667–670.

Gregg C, Zhang J, Weissbourd B et al. (2010) High‐resolution analysis of parent‐of‐origin allelic expression in the mouse brain. Science 329: 643–648.

Hark AT, Schoenherr CJ, Katz DJ et al. (2000) CTCF mediates methylation‐sensitive enhancer‐blocking activity at the H19/Igf2 locus. Nature 405: 486–489.

Johnson DR (1974) Hairpin‐tail: a case of post‐reductional gene action in the mouse egg. Genetics 76: 795–805.

Kaneda M, Okano M, Hata K et al. (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429: 900–903.

Koerner MV and Barlow DP (2010) Genomic imprinting‐an epigenetic gene‐regulatory model. Current Opinion in Genetics & Development 20: 164–170.

Kurukuti S, Tiwari VK, Tavoosidana G et al. (2006) CTCF binding at the H19 imprinting control region mediates maternally inherited higher‐order chromatin conformation to restrict enhancer access to Igf2. Proceedings of the National Academy of Sciences of the USA 103: 10684–10689.

Lewis A, Mitsuya K, Umlauf D et al. (2004) Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nature Genetics 36: 1291–1295.

Li E, Beard C and Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366: 362–365.

Li X, Ito M, Zhou F et al. (2008) A maternal‐zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Developmental Cell 15: 547–557.

Li Y and Sasaki H (2011) Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming. Cell Research 21: 466–473.

Lopes S, Lewis A, Hajkova P et al. (2003) Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long‐range chromatin interactions. Human Molecular Genetics 12: 295–305.

McEwen KR and Ferguson‐Smith AC (2010) Distinguishing epigenetic marks of developmental and imprinting regulation. Epigenetics & Chromatin 3: 2.

McGrath J and Solter D (1984) Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37: 179–183.

Moore T and Haig D (1991) Genomic imprinting in mammalian development: a parental tug‐of‐war. Trends in Genetics 7: 45–49.

Morison IM, Ramsay JP and Spencer HG (2005) A census of mammalian imprinting. Trends in Genetics 21: 457–465.

Nagano T, Mitchell JA, Sanz LA et al. (2008) The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322: 1717–1720.

Nakamura T, Arai Y, Umehara H et al. (2007) PGC7/Stella protects against DNA demethylation in early embryogenesis. Nature Cell Biology 9: 64–71.

Nativio R, Wendt KS, Ito Y et al. (2009) Cohesin is required for higher‐order chromatin conformation at the imprinted IGF2‐H19 locus. PLoS Genetics 5: e1000739.

Ooi SK, Qiu C, Bernstein E et al. (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448: 714–717.

Reik W and Walter J (2001) Genomic imprinting: parental influence on the genome. Nature Reviews Genetics 2: 21–32.

Renfree MB, Hore TA, Shaw G, Graves JA and Pask AJ (2009) Evolution of genomic imprinting: insights from marsupials and monotremes. Annual Review of Genomics and Human Genetics 10: 241–262.

da Rocha ST, Edwards CA, Ito M, Ogata T and Ferguson‐Smith AC (2008) Genomic imprinting at the mammalian Dlk1‐Dio3 domain. Trends in Genetics 24: 306–316.

Rodriguez‐Paredes M and Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nature Medicine 17: 330–339.

Searle AG and Beechey CV (1978) Complementation studies with mouse translocations. Cytogenetics and Cell Genetics 20: 282–303.

Sharman GB (1971) Late DNA replication in the paternally derived X chromosome of female kangaroos. Nature 230: 231–232.

Sleutels F, Zwart R and Barlow DP (2002) The non‐coding air RNA is required for silencing autosomal imprinted genes. Nature 415: 810–813.

Smits G, Mungall AJ, Griffiths‐Jones S et al. (2008) Conservation of the H19 noncoding RNA and H19‐IGF2 imprinting mechanism in therians. Nature Genetics 40: 971–976.

Surani MA, Barton SC and Norris ML (1984) Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308: 548–550.

Takagi N and Sasaki M (1975) Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 256: 640–642.

Terranova R, Yokobayashi S, Stadler MB et al. (2008) Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Developmental Cell 15: 668–679.

Weksberg R, Shuman C and Beckwith JB (2010) Beckwith–Wiedemann syndrome. European Journal of Human Genetics 18: 8–14.

Wood AJ, Roberts RG, Monk D et al. (2007) A screen for retrotransposed imprinted genes reveals an association between X chromosome homology and maternal germ‐line methylation. PLoS Genetics 3: e20.

Wood AJ, Schulz R, Woodfine K et al. (2008) Regulation of alternative polyadenylation by genomic imprinting. Genes & Development 22: 1141–1146.

Further Reading

Bartolomei MS and Ferguson‐Smith AC (2011) Mammalian genomic imprinting. Cold Spring Harbor Perspectives in Biology [Epub ahead of print].

Feng S, Jacobsen SE and Reik W (2010) Epigenetic reprogramming in plant and animal development. Science 330: 622–627.

Ferguson‐Smith AC (2011) Genomic imprinting: the emergence of an epigenetic paradigm. Nature Reviews Genetics 12: 565–575.

Ferron SR, Charalambous M, Radford E et al. (2011) Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475: 381–385.

Garfield AS, Cowley M, Smith FM et al. (2011) Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature 469: 534–538.

Odom LN and Segars J (2010) Imprinting disorders and assisted reproductive technology. Current Opinion in Endocrinology, Diabetes and Obesity 17: 517–522.

Santoro F and Barlow DP (2011) Developmental control of imprinted expression by macro non‐coding RNAs. Seminars in Cell & Developmental Biology [Epub ahead of print].

Schulz R, Proudhon C, Bestor TH et al. (2010) The parental non‐equivalence of imprinting control regions during mammalian development and evolution. PLoS Genetics 6: e1001214.

Watanabe T, Tomizawa S, Mitsuya K et al. (2011) Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 332: 848–852.

Web Links

King's College London. WAMIDEX: A Web Atlas of Murine Genomic Imprinting and Differential Expression. https://atlas.genetics.kcl.ac.uk

MRC Mouse Book. Catalog of Imprinting Features. http://s.php? catalog=imprinting

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
da Rocha, Simão Teixeira, and Heard, Edith(Nov 2011) Genomic Imprinting at the Transcriptional Level. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005686.pub2]