Genomic Imprinting

12 Key excerpts on "Genomic Imprinting"

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  Genes in Conflict

  The Biology of Selfish Genetic Elements

  • Austin Burt, Robert Trivers, Austin BURT(Authors)
  • 2009(Publication Date)
  • Belknap Press

    (Publisher)

  Genomic Imprinting Genomic Imprinting RESULTS in parent-specific gene expression, that is, in a difference in gene expression depending on which parent contributed the gene. In the usual case, an allele is silent when inherited from one parent while the identical stretch of DNA is active if inherited from the other; but often this effect is seen in some tissues and not others, or there is only a quantitative difference in gene expression, depending on the parent of ori-gin. To give but one example, in the mouse Meg1/Grb10 shows maternal ex-pression in most tissues, but paternal expression in the brain; in humans it also shows paternal expression in the brain, but biallelic expression in other tissues (Kaneko-Ishino et al. 2003). Because the difference in expression oc-curs when DNA is identical, the effect is said to be “epigenetic,” that is, the difference is caused by some aspect of the chemistry of the proteins binding DNA or of the DNA itself, but unrelated to nucleotide sequence. Such genes are said to be imprinted. This ability to be expressed according to parent-of-origin has striking im-plications for a gene’s degree of relatedness to its parents—and, thus, to all other relatives differentially related through them. Consider an autosomal gene’s relatedness to its mother. An unimprinted gene has no information where it came from and computes only the average chance of one-half. An imprinted gene calculates exact relatedness, maternal = 1, paternal = 0. These sharply divergent kinship coefficients create 2 kinds of conflict. One occurs over evolutionary time in which the spread of selfish paternally ac-96 tive genes naturally selects for opposing maternally active genes (and vice versa), while both select (albeit less strongly) for opposing unimprinted genes. The second kind of conflict is imagined to occur within an individual whenever the opposing genes act against each other.

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  Epigenetic Gene Expression and Regulation

  • Suming Huang, Michael D. Litt, C. Ann Blakey, Michael D Litt(Authors)
  • 2015(Publication Date)
  • Academic Press

    (Publisher)

  Chapter 3

  Genomic Imprinting in mammals—memories of generations past

  Nora Engel     Fels Institute for Cancer Research, Temple University School of Medicine, Philadelphia, PA, USA

  Abstract

  Genomic Imprinting in mammals is the process by which the nonequivalence of parental genomes is established, leading to parent-of-origin effects on several processes, including transcription. Establishment and maintenance of imprints is needed for viability and healthy embryogenesis. DNA methylation has the dual role of marking genes as either maternally or paternally inherited and of silencing gene expression on one of the two alleles. Furthermore, imprinting control extends over large domains of genes by mechanisms that have yet to be elucidated. Studies of imprinted regions have revealed many of the broader principles of the epigenetic control of transcription, including silencing mechanisms and the role of noncoding RNAs. Since imprinted genes are functional haploids, disruption of the one active allele can lead to a variety of developmental diseases, behavioral disorders, and cancer. Comparative and evolutionary studies to determine how and why imprinting came about have generated several hypotheses that are still under debate.

  Keywords

  DNA methylation; Epigenetics; Genomic Imprinting; Monoallelic expression

  Contents

  1. Introduction  43

  2. The life cycle of imprinted regions  44

  3. Mechanisms of Genomic Imprinting  46

  4. Top-down dissection of imprinted domains  49

  5. Transcriptional interpretation of the imprint  50

  6. Imprinting and human disease  52

  7. Finding new imprinted genes  54

  8. The evolution of imprinting  54

  8.1 The how  54

  8.2 The why  55

  9. Conclusion  57

  Acknowledgments  57

  References  57

  1. Introduction

  Mammals are diploid organisms consisting of two parental genomes that are functionally distinct. The maternal and paternal genomes are different in their potential for gene expression because of sex-specific specializations that are imposed on the DNA during oogenesis and spermatogenesis. Additional differences may occur after fertilization, before the two genomes are united. These differences are determined by epigenetic mechanisms, i.e., reversible chemical and structural modifications that are applied to the DNA and can affect the transcriptional competence of genes, without altering the DNA sequence per se

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  Seed Genomics

  • Philip W. Becraft(Author)
  • 2013(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  4 Epigenetic Control of Seed Gene Imprinting Christian A. Ibarra, Jennifer M. Frost, Juhyun Shin, Tzung-Fu Hsieh, and Robert L. Fischer Introduction

  Genomic Imprinting is a process found in mammals and flowering plants and is defined as the monoallelic expression of a gene in a parent-of-origin dependent manner. Imprinting is established epigenetically because the two alleles of an imprinted gene are identical in DNA sequence but differ in expression state. Epigenetic marks, mainly DNA methylation and histone modifications, are often associated with repressed chromatin and reside on specific parental alleles resulting in transcriptional silencing (Allis et al. , 2007). In both plants and mammals, most genomic imprints are established after meiosis in the gametes and, for the most part, remain after fertilization. To date, the number of imprinted genes in mammals is ∼120, representing <1% of the genes in the genome (Glaser et al. , 2006).

  In the case of the flowering plant Arabidopsis thaliana , the current number of imprinted genes is ∼50, a finding resulting from several more recent high-throughput allele-specific transcriptome studies (Tiwari et al. , 2010; Gehring et al. , 2011; Hsieh et al. , 2011; McKeown et al. , 2011; Wolff et al. , 2011). Similar genome-wide imprinting screens in maize (Waters et al. , 2011) and rice (Luo et al. , 2011) have also greatly increased the number of known imprinted genes in these agriculturally significant monocots. As described subsequently, the plant-imprinting field has graduated to the “omics” era, as a considerable number of transcriptome, methylome, and epigenome studies have appeared in the literature in the last few years.

  Genomic Imprinting and Parental Conflict Theory Parental Conflict Theory

  Genomic Imprinting is a process that results in only a single allele of a gene being expressed. As such, it seems a precarious evolutionary choice, reducing the robustness of the genome and potentially reducing the fitness of the organism. This is especially so in the case of imprinted genes, which have been shown to be indispensible for mammalian and plant development (Huh et al.

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  Epigenetics

  • Lyle Armstrong(Author)
  • 2020(Publication Date)
  • Garland Science

    (Publisher)

  Chapter Eleven

  The Epigenetic Basis of Gene Imprinting

  11.1 CONTROLLING MONOALLELIC EXPRESSION OF IMPRINTED GENES 11.2 EXAMPLES OF IMPRINTING 11.3 ESTABLISHING DIFFERENTIALLY METHYLATED REGIONS 11.4 THE NEED FOR IMPRINTING

  Another cellular function that seems to be subject to epigenetic control is Genomic Imprinting. This phenomenon is observed in mammals and many species of plants, and it has been suggested that this may serve to promote the survival of genes from one parent at the expense of the other. How this might relate to the way in which organisms continue to evolve is a matter of debate, but the imprinting phenomenon is still a good example of the epigenetic control of gene expression.

  Genomic Imprinting refers to monoallelic gene expression that occurs in a manner that is specific to the parent of origin. For the vast majority of genes present in the human genome, expression occurs from both alleles simultaneously (provided, of course, that expression is permitted in the cell type of interest); however, a small percentage (less than 1%) of genes are expressed from only one allele. Because each of these alleles is derived from a different parent, the imprinted genes are sometimes described as being maternally or paternally imprinted. For example, the gene encoding insulin-like growth factor 2 (IGF2/Igf2 ) is expressed only from the allele inherited from the father and thus is paternally imprinted. Shortly before completion of this book, the total number of imprinted genes in humans was 90, although the consensus of opinion is that more remain to be discovered.

  The basis of imprinting seems to be epigenetic. Although the precise nature of the initial epigenetic imprint is currently a matter of intense investigation, it is assumed that the parental imprint is set in the germ line, because this is the time when the genomes are in distinct compartments and can be differentially modified. It is worth noting that although a number of imprinted genes remain imprinted throughout the life of the organism, many genes are imprinted in a tissue-specific or temporal-specific way.

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  The Social Evolution of Human Nature

  From Biology to Language

  • Harry Smit(Author)
  • 2014(Publication Date)
  • Cambridge University Press

    (Publisher)

  The discovery that genes can be switched on and off helped us to understand how gene expression was regulated during ontogenesis (and other stages of the life cycle of a member of a species). For it was now easy to see that a similar process is in use for regulating the timing of the action of genes. If, for example, at a certain developmental stage the product of a certain gene was needed, it was conceivable that, because of the previous steps in the developmental programme, a produced protein could trigger the transcription of this gene and its production could affect the next step in the developmental pro- gramme. Epigenetics is the field in which the regulation and modulation of gene expression is studied. One of the proximate mechanisms involved in the regulation of gene expression is DNA methylation (Kelsey and Feil, 2013; Reik and Walter, 2001). It means that especially the cytosine bases in the DNA are 66 Inclusive fitness theory and Genomic Imprinting methylated, i.e. methyl groups are attached to bases in the DNA with the effect that expression of the gene is repressed or activated (switched off or on). The attachment of methyl groups is a reversible process, for attached molecules may be removed during later stages in the life cycle. Methylation of DNA is involved in Genomic Imprinting. In Genomic Imprinting it is the sex of the parent that determines gene expression (see Hall, 1997; Ohlsson, 1999; Ohlsson, Hall and Ritzen, 1995; Reik and Surani, 1997; Wilkins, 2009). It brings about that the expression of a gene depends on its methylation pattern (the pattern of methyl groups attached to a gene). This methylation pattern is called an imprint. The imprint determines whether a gene is switched on or off. But in contrast to other forms of gene regulation, the environmental factor is the sex of the parent: only the sex of the parent determines whether a gene gets an imprint or not.

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  Human Preimplantation Embryo Selection

  • Jacques Cohen, Kay Elder, Jacques Cohen, Kay Elder(Authors)
  • 2007(Publication Date)
  • CRC Press

    (Publisher)

  Genomic Imprinting AND CONSEQUENCES FOR EMBRYONIC DEVELOPMENT the mother’s own interests and future gestational activity. For example, the maternally derived copy of a gene product involved with the promotion of fetal growth, insulin-like growth factor 2 ( Igf2 ), is imprinted to an inactive state, effectively reducing the dosage of this gene. 16 Conversely, the gene for the Igf2 receptor (which binds to and inactivates Igf2 ) is inactivated on the paternal chromosome. This is a perfect example of a genomic ‘tug-of-war’ between the promotion and suppression of fetal growth. The result is that a complement of imprinted mammalian genes is only active in a single copy – the one bearing the active parent-of-origin imprint. As is discussed, dosage control for these genes is critical to normal development and perturbation to the process can have critical consequences. EPIGENETICS: MECHANISTIC CONCERNS A thorough description of epigenetic mechanisms from a molecular standpoint is well beyond the scope of this review. Epigenetic control mechanisms are among the most complex in molecular genetics, and are still only partly understood. 1,6,17 For the most part, epigenetic silencing or activation involves stable covalent modification to the chromatin, creat-ing specific states that have an over reaching effect on other mechanisms of expression control. Two hall-mark epigenetic chromatin modifications are cytosine methylation (at CpG sequences) and methylation/ acetylation of histone proteins. 18,19 Generally, the genome is divided into heavily methylated regions that are silent, and hypomethylated regions that are actively transcribed. However, as discussed below, in some cases uniquely methylated control regions are associated with gene activation. Cytosine methylation seems to be the principal protection mechanism for silencing foreign DNA (viral sequences, retrotrans-posons, etc.) in the genome, and such sequences are heavily methylated.

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  Beyond Sex Differences

  Genes, Brains and Matrilineal Evolution

  • Eric B. Keverne(Author)
  • 2017(Publication Date)
  • Cambridge University Press

    (Publisher)

  In this way, regardless of sex, some imprinted autosomal genes are only expressed when they originate from the mother, whereas others are expressed only when they originate from the father. The most prevalent mechanism for Genomic Imprinting 53 53 determining Genomic Imprinting is brought about by an ‘epigenetic’ chromosomal mark, the imprint control region or ICR. This meth- ylation mark on DNA is heritable through the matriline, thereby providing the mother’s genome with control over which imprinted allele is expressed, maternal or paternal (Bourc’his & Bestor, 2006). Paternal expression occurs when the ICR is of maternal origin, but when this ICR regulates inhibitory non-coding micro-RNAs embed- ded in the imprinted gene cluster, then maternal expression follows. Throughout mammalian evolution, more autosomal genes have been recruited to the ICR, thereby resulting in their imprinted expression. Moreover, a number of imprinted gene clusters also contain small non-coding RNAs which are regulated by the Drosha/Dgcr8 com- plex. These non-coding RNAs are gaining recognition in the context of brain development and psychiatric disorders, as well as in pla- cental development and placental dysfunctions, regions for which imprinted genes are heavily engaged. Historical Perspective on Genomic Imprinting The first indirect evidence for inheritance being governed by different ‘parent of origin’ autosomal genes – that is, genes not involving the XY sex chromosomes – arose from the study of hybrid mammalian crosses (Gray, 1972). These hybrids are produced by reciprocal cross- mating of different mammalian species and results in offspring of the same genetic make-up, but which differ in appearance according to parental mating. Thus, when a male horse (stallion) is mated with a female donkey, a ‘hinny’ is produced, and conversely if a female horse (mare) is mated with a male donkey, a ‘mule’ is produced.

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  Epigenetics and Epigenomics

  • Christopher J. Payne(Author)
  • 2014(Publication Date)
  • IntechOpen

    (Publisher)

  Genetics 2007; 175(1) 1-6. Epigenetics and Epigenomics 142 [13] Surani M.A., Barton S.C., Norris M.L., Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 1984; 308(5959) 548-550. [14] McGrath J., Solter D. Completion of mouse embryogenesis requires both maternal and paternal genomes. Cell 1984; 37(1) 179-183. [15] Devriendt K., Hydatidiform mole and triploidy: the role of Genomic Imprinting in placental development. Human Reproduction Update 2005; 11(2) 137-142. [16] Golubovsky M.D., Postzygotic diploidzation of triploids as a source of unusual cases of mosaicism, chimerism and twinning. Human Reproduction 2003; 18(2) 236-242. [17] Reik W., Fean W., Walter J. Epigenetic reprogramming in mammalian development. Science 2001; 293(5532) 1089-1093. [18] Li E., Chromatin modification and epigenetic reprogramming in mammalian devel‐ opment. Nature Reviews Genetics 2002; 3(9) 662-673. [19] Reik W., Walter J., Genomic Imprinting: parental influence on the genome. Nature Re‐ views Genetics 2001; 2(1) 21-32. [20] Arnaud P., Feil R., Epigenetic deregulation of Genomic Imprinting in human disor‐ ders and following assisted reproduction. Birth Defects Research (Part C) 2005; 75(2) 81-97. [21] Geneimprint. Imprinted genes database: http://www.geneimprint.com/site/genes-by-species.Homo+sapiens.imprinted-All (Accessed 29 August 2013). [22] Tycko B., Morison I.M., Physiological functions of imprinted genes. Journal of Cell Physiology 2002; 192(3) 245-258. [23] Haig D., Graham C., Genomic Imprinting and the strange case of the insulin-like growth factor II receptor. Cell 1991; 64(6) 1045-1046. [24] Cattanach B.M., Jones J., Genetic imprinting in the mouse: Implications for gene reg‐ ulation. Journal of Inherited Metabolic Disease 1994; 17(4) 403-421. [25] Henderson D.J., Sherman L.S., Loughna S.C. et al., Early embryonic failure associated with uniparental disomy for human chromosome 21.

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  Gene Regulation, Epigenetics and Hormone Signaling

  • Subhrangsu S. Mandal(Author)
  • 2017(Publication Date)
  • Wiley-VCH

    (Publisher)

  However, there are discrepancies about the identity of the primordial epigenetic marks. Parent-of-origin-dependent DNA methylation can be reprogrammed in the gametes and has been associated with the control of many imprinted genes, but not all. The complexity of the elements and mechanisms involved in imprinting control obscures the identification of the primordial imprinting marks. Histone modifications are good candidates, although the nature of such primordial modifications remains to be determined. Additional layers of complexity are provided by trans -effects on imprinted loci, due to protein (such as CTCF) binding, chromatin position, and interactions, some possibly affecting multiple genes or networks. Given the importance of imprinting in development and health, there is a great interest on understanding how it is controlled. Step by step, imprinting studies are allowing us to interpret the multifaceted regulatory mechanisms and interactions that underlie the surprising diversity of imprinted expression patterns. Future studies will also unveil the molecular changes that originally triggered differences between the expression of maternally and paternally inherited copies of genes. Acknowledgments I apologize to all the colleagues whose original research papers could not be cited due to space limitations. I would like to thank José Javier García Ramírez for his helpful comments to this manuscript. ECE is supported by the INCRECYT Program of the Junta de Comunidades de Castilla-La Mancha and the European Social Funds. References 1 Barton, S.C., Surani, M.A., and Norris, M.L. (1984) Role of paternal and maternal genomes in mouse development. Nature, 311, 374–376. 2 Cattanach, B.M. and Kirk, M. (1985) Differential activity of maternally and paternally derived chromosome regions in mice. Nature, 315, 496–498. 3 Searle, A.G. and Beechey, C.V. (1990) Genome imprinting phenomena on mouse chromosome 7. Genet

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  Cancer Epigenetics

  • Trygve Tollefsbol(Author)
  • 2008(Publication Date)
  • CRC Press

    (Publisher)

  Before proceeding to a discussion of alterations in imprinting during tumorigenesis, it is appropriate to fi rst brie fl y de fi ne how imprinted gene expression is regulated. Central to the mechanism of imprinted gene regulation are regions marked epigenetically by DNA methylation. Epigenetic modi fi cations include non-sequence changes of both DNA (methylation) and histone 51 proteins (acetylation, methylation, phosphorylation, and ubiquitinylation, for an excellent review of epigenetic modi fi cations, see Ref. [3]). These hereditable and generally reversible modi fi cations are located in precise locations within imprinted gene loci, referred to as imprinting control regions (ICRs) or differentially methylated regions (DMRs). Only one of the two ICR alleles is methylated, consti-tuting the molecular signature by which the two alleles are distinguished. An understanding of the initial marking of imprinted regions during gonocyte development provides insight into possible mechanisms by which LOI may arise in cancer (for review see Ref. [4]). In the following sections we present the developmental events of imprint marking, ‘‘ reading ’’ mechanisms of imprint marks, chromatin modi fi cations associated with imprinted loci, biological function of imprinted genes, human syndromes exhibiting altered imprinted gene expression, incidence of LOI in human cancers, and fi nally lesions leading to LOI. 4.1.1 D EVELOPMENTAL E STABLISHMENT OF I MPRINTING M ARKS Both maternal and paternal marks are established during the development of their respective gonocytes, oocytes, and sperm. Figure 4.1 provides a temporal scheme of these events in the mouse. At approximately 10.5 days of embryonic development (E10.5), primordial gonocytes have fi nished migrating to the germinal ridge. Shortly thereafter, all DNA methylation is erased, regardless of parental origin [5]. The primordial gonocytes will then diverge towards either oocyte or sperm development.

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  Advances in Developmental Biology

  • Paul Wassarman(Author)
  • 1993(Publication Date)
  • Elsevier Science

    (Publisher)

  These include spino cerebellar ataxia (Harding, 1981) and myotonic dystrophy. Myotonic dystrophy maps to human chromosome 19, in a region which shows synteny with the proximal region of mouse chromo- some 7 (Saunders and Seldin, 1990). A more extensive list of human diseases that may show a parent-of-origin effect can be found in a review by Hall (1990). XIII. CONCLUSIONS Genomic Imprinting is now a recognized phenomenon having a profound role in the development of mammalian embryos. There is an absolute requirement that paternally and maternally derived chromosomes must be present together in the same cell for embryos to develop properly. To be diploid, with either only maternal or paternal chromosomes, is insufficient. Paternal chromosomes appear to be necessary for normal development of the trophoblast and to sustain certain somatic cell lineages in later stages of postimplantation development. It is not understood what determines the loss of cells in parthenogenetic embryos, but there is a loose correlation with the onset of tissue differentiation. Maternally derived chromosomes are essential since androgenetic embryos also die, although their abnormal development is different to that seen in the partheno- genetic embryos. Analysis of the development of androgenetic embryos or chime- ras has suggested that abnormal development may be due to overgrowth of certain tissues such as the trophectoderm, as seen in hydatidiform mole and the costal rib cartilage in chimeras. This may be due to the overproduction of growth factors, such as IGF 11, or a lack of factors required to constrain growth, or both. 108 COLIN L. STEWART Indeed, it is remarkable, as Cattanach has already commented, that so many of the examples of imprinting appear to involve growth (Cattanach and Beechey, 1990). If imprinting has evolved as a means to regulate embryonic growth, then it is necessary to determinewhy it should apparently be restricted, among vertebrates, to mammals.

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  Epigenetics

  Linking Genotype and Phenotype in Development and Evolution

  • Benedikt Hallgrimsson Ph.D., Brian K. Hall Ph.D., Benedikt Hallgrimsson Ph.D., Brian K. Hall Ph.D.(Authors)
  • 2011(Publication Date)
  • University of California Press

    (Publisher)

  Whether these in situ findings can be replicated in laboratory growth chambers remains to be seen. CONCLUSION Epigenesis, the gradual unfolding of develop-mental trajectories in which succeeding changes depend on preceding ones, has many sources of coordination. Self-organizing properties of physical and geometric constraints, stochastic processes, morphogenetic fields, and external environments all contribute to epigenesis, along with genomes containing encoded properties. The relationship of genotype and phenotype during development is presented here as a re-ciprocal, dynamic interaction in which gene ex-pression depends on developmental context and developmental context is shaped by gene expres-sion. Without a genome, development would grind to a halt; without developmental context, the genome is quite powerless to affect form. Epigenesis as a conceptual framework provides a natural approach to describing and analyzing dynamic developmental processes at many lev-els of organization, without an implicit bias as to what factors are driving the process. Epige-netic phenomena highlight the challenge ahead and demonstrate that our quest for a genotype-to-phenotype “map” will require more than cor-relations of coding motifs to structures. We will need to ask the question of what else, in addi-tion to a genotype, is required to arrive at a par-ticular phenotype and to consider whether, in the origination of biological form, adaptive fea-tures that were not initially genetically encoded may have been “captured” by genes to increase the frequency with which those forms appeared (Muller and Newman, 2003; Newman and Muller, 2000). The best systems to address these issues may yet prove to be those in which the interaction of more than one genome yields an emergent phenotype. B A C FIGURE 7.3 Galls (arrows) on three plants of the goldenrod Solidago canadensis . ( A ) The elliptical stem gall caused by the larva of the moth Epiblema scudderiana .

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