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Genomic Imprinting Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press COMMENTARY Genomic imprinting Genomic imprinting is the differential modification of sine content in the DNA of the sperm and the egg, and the maternal and paternal genetic contributions to the this has been proposed as a possible molecular basis for zygote, resulting in the differential expression of pa­ imprinting (Monk 1987; Monk et al. 1987). Normally, it rental alleles during development and in the adult. It has is not possible to distinguish the levels of methylation of been known for some time that imprinting plays a role different parental genomes, or specific alleles, in the in­ in a diversity of biological phenomena, including sex de­ dividual. Therefore, transgenic marker sequences, inte­ termination and germ cell differentiation in certain in­ grated at various sites in the genome and inherited from sects (Brown and Nur 1964; Scarbrough et al. 1984), pref­ one or the other parent, have been used to show differ­ erential inactivation of the paternal X chromosome in ential methylation. The frequency of differential meth­ marsupials (for review, see VandeBurgh et al. 1987) and ylation of different transgenes has been reported in 4 out in the extraembryonic membranes of rodents (Takagi of 5 transgene loci studied by Sapienza et al. (1987), 1 out and Sasaki 1975), uniparental inheritance of chloroplast of 7 studied by Reik et al. (1987), and 1 out of 10 studied DNA (Sager and Kitchin 1975), and mating-type inter- by Swain et al. (1987). In most cases, the transgene in­ conversion in fission yeast (Klar 1987). Lately, the phe­ herited from the father is less methylated than if it were nomenon of imprinting is exciting considerable interest. inherited from the mother. So far, for any of these trans­ This is due to the recent discoveries in the mouse that gene loci showing differential imprinting in the fetus or the differential modification of the maternal and pa­ adult, it is not known whether the difference also ex­ ternal genomes is essential for successful development isted earlier between the sperm and the ^gg (because of of the conceptus (McGrath and Solter 1984; Surani et al. the difficulty in obtaining enough oocyte DNA for anal­ 1984) and survival and normal phenotype of the adult ysis); but in three cases examined by the workers men­ (Cattanach and Kirk 1985). In addition, recent reports tioned above, undermethylation of the paternally inher­ that transgenic DNA marker sequences are methylated ited loci in the offspring is reflected by undermethyla­ differently, depending on the parent of origin, suggest tion of these loci in the testes. This would seem to be at that methylation may be involved in the mechanism of variance with the fact that sperm DNA is more methyl­ imprinting (Reik et al. 1987; Sapienza et al. 1987; Swain ated than oocyte DNA overall. However, irrespective of et al. 1987). The regions of chromatin involved are now overall genomic methylation differences, imprinting accessible to further analysis. may be due to differential modulation of methylation The investigations that have shown a requirement for along particular domains of sperm and oocyte DNA. A the differentially modified maternal and paternal genetic precedent for differential modulation of methylation is contributions for successful development and normal seen, e.g., between the active and inactive X chromo­ phenotype in the mouse have utilized duplications of somes in somatic tissues; clustered CpG sequences 5' to maternal or paternal genomes or chromosome regions. certain genes are more methylated the compared to in­ Mouse embryos containing either two female pronuclei active X chromosome, whereas other CpG sequences in or two male pronuclei were created by exchange of pron­ the body of the gene are less methylated on the inactive uclei between eggs (Barton et al. 1984; Mann and Loveil- X chromosome. The inactive X chromosome also re­ Badge 1984; McGrath and Solter 1984; Surani et al. minds us that there are more ways to inactivate a chro­ 1984). In embryos with two female genetic comple­ mosome or chromosomal domain than methylation ments, fetal development was good but development of alone; chromosome configuration must also play a part the extraembryonic membranes and placenta was poor; in maintaining inactivation in segmental fashion along in embryos with two male genetic complements, the re­ the inactive X chromosome (for review, see Monk 1986). verse was true—the extraembryonic tissues developed Imprinting must be established during (or before) ga- well, and the fetus developed poorly. The reason for the metogenesis, persist stably throughout DNA replication uneven contribution to the different parts of the con­ and cell division in the soma, and be erased in the germ ceptus is not yet understood. Duplications of maternal line to be differentially established once more in the or paternal specific chromosome regions may be sperm and tgg genomes. Stable, heritable, differential achieved by matings between mice with different chro­ modification of chromatin is required. Differential pat­ mosome translocations (Searle and Beechey 1978) or car­ terns of methylation are stable, heritable (HoUiday and rying different metacentric chromosomes (Cattanach Pugh 1975), and, moreover, have been implicated in the and Kirk 1985). The combinations may be lethal or re­ regulation of gene expression, chromatin configuration, sult in different phenotypes, suggesting differential and X-chromosome expression. The configurational dif­ functioning of maternal and paternal gene loci within ferences between repressed and derepressed chromo­ the regions concerned. Again, the loci involved and the some domains are also heritable (Weintraub 1985) and causes of the anomalies are unknown. correlated with methylation (Keshet et al. 1986). Sperm In the mouse, there is a difference in the methyl cyto- and oocyte are methylated differently; they are also sub- GENES & DEVELOPMENT 2:921-925 © 1988 by Cold Spring Harbor Laboratory ISSN 0890-9369/88 $1.00 921 Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Monk ject to different configurational constraints in the pack­ }— ^^ sperm aging of their genomes. Therefore, I would like to pro­ pose a model of establishment, propagation, and erasure GAMETES of imprinting that works on at least two different levels ijlTr —differential methylation and differential chromatin 1 1 8 cell configuration. Three important aspects of this model CLEAVAGE follow: (1) Initial imprinting differences between the ga­ metes influence the timing of onset of parental allele ex­ pression. Thereafter, 'function determines form' in the 1 1 ICM sense that recruitment of specific maternal or paternal 1 bla 1 domains of chromatin into active gene expression during BLASTOCYST development leads to 'open' chromatin configuration in these regions and undermethylation. Conversely, the failure of a specific maternal or paternal chromosome 1 1 ICM 1 bla 1 domain to enter active expression during certain in­ IMPLANTATION terval of time in development may lead to condensation and subsequent methylation of that domain. (2) The Lyt germ line escapes extensive de novo DNA methylation, 1 6''i epj 1 6^a tr\i PRE-GA5TRULATI0N and this hypomethylation is a prerequisite or a precon­ 1 dition for erasure of the configurational constraints of imprinting and for reprogramming of the germ line to developmental totipotency; this process may be con­ 1 /~V^ 7^2 emb 1 7^ cho nected to meiosis. (3) Some apparent differential im­ GASTRULATION printing phenomena (preferential allele expression, ab­ normal phenotype, or nonreciprocal lethality) may be a consequence of DNA sequence differences between the 1 GC^ \ 1 GCc/ maternal and paternal chromosome regions concerned. GERM CELLS Further considerations related to this model are out­ lined below. We have studied the temporal and regional changes in Figure 1. Densitometer tracings of DNA isolated from dif­ overall DNA methylation in the embryonic, extraem­ ferent tissues of the mouse conceptus and digested with Hpflll. bryonic, and germ cell lineages during development of Fragments resulting from Hpflll digestion were end-labeled, the mouse (Monk et al. 1987; Sanford et al, 1987). A electrophoresed, blotted to a nitrocellulose filter, and autora- summary of the results is given in Figure 1 in the form of diographed. The discrete band in the oocyte track is one of the densitometer tracings of the distributions of the larger mitochondrial Hpflll fragments. (ICM) Irmer cell mass; (bla) fragment sizes resulting from Hp^II digestion of DNA blastocyst; (epi) epiblast; (end) primary endoderm; (emb) em­ bryo; (cho) chorion; (GC) germ cell; 6.5 and 7.5, days of gesta­ from eggs, sperm, eight-cell embryos, blastocysts and tion. (For details, see Monk et al. 1987.) implanting blastocysts (and their isolated inner cell masses), embryonic and extraembryonic regions of pos- timplantation embryos (pre- and postgastrulation), and premeiotic germ cells of male and female embryos. In­ ating or confirming differential programming of the de­ creased genomic methylation (e.g., sperm and gastru- finitive germ layers. We proposed that much of the de lating embryo DNAs; Fig. 1) is correlated with higher- novo methylation observed in somatic tissues acts to molecular-weight Hpall fragments to the left of the dis­ stabilize and reinforce prior events regulating the ac­ tributions (top of the lanes on the gel) and decreased tivity of specific genes, chromosome domains, or the X genomic methylation, with a skewing of the distribution chromosome (in females). A similar conclusion—that away from the top of the gel (e.g., oocyte, blastocysts, methylation may be a secondary event involved in fetal germ cell DNAs; Fig. 1). It is clear that the Qgg maintenance of the inactive state—was reached by Lock genome is strikingly undermethylated (the peak fraction et al. (1987), who showed that methylation of gene se­ is a Hpall fragment of mitochrondrial DNA) and the quences on the inactive X chromosome occurred after sperm genome is relatively methylated.
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