Genomic Imprinting at the Transcriptional Level

Simão Teixeira da Rocha, Institut Curie, Paris, France
Edith Heard, Institut Curie, Paris, France

Published online: November 2011

DOI: 10.1002/9780470015902.a0005686.pub2

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, 2001).
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.
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Related Sub-Topics:

Genes, Molecules and Cellular Processes | Developmental Disorders | Genomic Disorders | Epigenetics and Disease | Transcriptional Regulation | Chromosomes and Chromatin Modifications | Evolution of Coding and Functional Modules
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Article Title: Genomic Imprinting at the Transcriptional Level
 
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]