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The Discovery and Importance of Genomic Imprinting

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The Discovery and Importance of Genomic Imprinting FEATURE ARTICLE 2018 GAIRDNER AWARDS The discovery and importance of genomic imprinting Abstract The discovery of genomic imprinting by Davor Solter, Azim Surani and co-workers in the mid-1980s has provided a foundation for the study of epigenetic inheritance and the epigenetic control of gene activity and repression, especially during development. It also has shed light on a range of diseases, including both rare genetic disorders and common diseases. This article is being published to celebrate Solter and Surani receiving a 2018 Canada Gairdner International Award "for the discovery of mammalian genomic imprinting that causes parent-of-origin specific gene expression and its consequences for development and disease". ANNE C FERGUSON-SMITH AND DEBORAH BOURC’HIS Imprinted genes in development, of an imprinted gene – either the copy inherited epigenetics and disease from the father or the copy inherited from the n 1984, Davor Solter (working with James mother. It later emerged that the imprinting I McGrath at the Wistar Institute in Philadel- marks were epigenetic modifications phia) and, independently, Azim Surani (work- (in particular, DNA methylation). ing with Sheila Barton and Michael Norris at the Around the same time, genetic studies by AFRC Institute of Animal Physiology in Cam- Bruce Cattanach and Michael Kirk showed that bridge) published the results of experiments on imprinted genes were not evenly distributed newly fertilized mouse eggs (McGrath and Sol- across the whole genome but located in particu- ter, 1984; Surani et al., 1984; Barton et al., lar genomic regions (Cattanach and Kirk, 1984). They had generated embryos that con- 1985). This finding was confirmed by the subse- tained either two sets of chromosomes inherited quent identification and mapping of imprinted from the mother, or two sets of chromosomes genes, although the first three imprinted genes, inherited from the father. However, when trans- Igf2r, Igf2 and H19, were not identified until ferred into pseudo-pregnant recipient females, 1991 (Barlow et al., 1991; DeChiara et al., the embryos failed to develop to term. 1991; Ferguson-Smith et al., 1991; These remarkable results sent a clear mes- Bartolomei et al., 1991). sage: despite being genetically equivalent, the Over the years, studies in mice and humans set of chromosomes inherited from the mother have shown that imprinted genes are essential were not functionally equivalent to the set inher- not only for the prenatal development of normal ited from the father. The defective development embryonic and extraembryonic components, as of the bi-maternal and the bi-paternal embryos demonstrated in the early experiments of Surani indicated that, for normal development to occur, and Solter, but also for postnatal processes that one set of chromosomes from each parent was include the regulation of the brain and behavior, required. This is due to a process called ’geno- metabolism, and physiological adaptations mic imprinting’ which acts in the gametes to (Cleaton et al., 2014). Moreover, a number of Copyright Ferguson-Smith and ’mark’ genes on the maternal and paternal chro- human syndromes exhibiting parent-of-origin Bourc’his. This article is distributed mosomes in order to ensure parent-of-origin effects in their patterns of inheritance were under the terms of the Creative specific expression after fertilization. All cells known, including the fetal overgrowth disorder Commons Attribution License, which contain two copies of every gene (except those Beckwith-Wiedemann Syndrome (which is also permits unrestricted use and genes found on the single Y chromosome in redistribution provided that the associated with an increased incidence of child- original author and source are males). In general both copies of a gene are hood tumors), and two neurological disorders credited. expressed. However, cells express only one copy (Prader-Willi Syndrome and Angelman Ferguson-Smith and Bourc’his. eLife 2018;7:e42368. DOI: https://doi.org/10.7554/eLife.42368 1 of 5 Feature article 2018 Gairdner Awards The discovery and importance of genomic imprinting Syndrome). These and other syndromes were proteins (such as CTCF), and has helped to found to be caused by the inheritance of two define many of the enzymatic processes that imprinted domains from the mother and none write, read and erase epigenetic states from the father, or vice versa; by deletions at (Barlow and Bartolomei, 2014; Ferguson- imprinted regions; or by a failure either to estab- Smith, 2011). lish a proper imprint during gamete production or to maintain it after fertilization. Such studies have, of course, been important Imprinted genes: a paradigm of for elucidating these imprinted disorders, but epigenetic regulation with genetic perhaps more importantly, they have implicated determinism imprinted genes more generally in pathways Where do we stand now, 34 years after the origi- that control the aetiology of much more com- nal discovery of genomic imprinting? High mon diseases, such as those involved in growth, throughput sequencing approaches – and their application to small numbers of cells – have metabolism, cancer and neurological disorders. been instrumental in revealing the developmen- We now know that genomic imprinting tal regulation and extent of genomic imprinting. involves the transmission of epigenetic informa- In particular, genome-wide profiling of tion, in the form of DNA methylation marks, gametic methylation in mice and humans has from gametes to offspring, with the result that a highlighted that thousands of sequences acquire set of around 100–200 genes (both protein cod- asymmetric DNA methylation states in the ing genes and non-coding RNA genes) are oocyte and spermatozoon, reflecting the con- expressed from only one of the two chromo- trasting biology of DNA methylation in the two somes in cells. The essential role for DNA meth- germlines (Smallwood et al., 2011; ylation in imprinting was shown through the Kobayashi et al., 2012). In males, sperm meth- inheritance of mutations in DNA methyltransfer- ylation preferentially targets intergenic sequen- ases (Bourc’his et al., 2001; Li et al., 1993; ces and transposon repeats. In females, oocyte Kaneda et al., 2004). These DNA methylation methylation coincides with the body of actively marks provide an imprint that is acted upon by a transcribed genes, including intragenic CpG hierarchy of transcriptional and chromatin states, islands (Veselovska et al., 2015). The distribu- including differential histone modifications on tion and genomic properties of ICRs do not dif- the two parental chromosomes (Fournier et al., fer from these genome-wide trends: maternal 2002), that result in the monoallelic expression ICRs all coincide with CpG island promoters of imprinted genes. located downstream of transcription start sites It also became clear that imprinted genes that are active during oocyte growth, while are often clustered around a single imprinting paternal ICRs have an intergenic location. ICRs control region (ICR) that influences the monoal- are not established as special regulators in the lelic expression of the whole cluster. Indeed, germline: rather they are selected, post-fertiliza- ICRs are regulatory sequences that control the tion, by being actively protected from the expression of genes that code for proteins, or genome-wide loss of methylation that occurs for long-non-coding RNAs that control the activ- before embryo implantation. ity of the cluster in cis. A transcription factor The realization that the epigenetic protection called CTCF also has an important role at some of ICRs was genetically determined came as a (but not all) of these clusters, to modulate the surprise. ICRs are endowed with several regulation of imprinted gene expression in a TGCCGC motifs and, when methylated, these parental-origin-specific manner. motifs are recognized by a zinc finger protein Hence, over the years, the analysis of differ- called ZFP57 which, in turn, recruits the KAP1- ential DNA methylation at imprinted domains centered heterochromatic complex has provided a paradigm in which to assess the (Quenneville et al., 2011). This allows for the links between particular epigenetic states and concentration of DNA methyltransferases the long- and short-range cis-acting control of around the ICRs and the propagation of their gene expression in mammals. These studies germline-methylation status in the early embryo, have uncovered regulatory relationships while the rest of the genome is undergoing between DNA methylation, histone modifica- global reprogramming. Upon complete deple- tions, long-non-coding RNAs and associated tion of ZFP57, multiple ICRs fail to maintain their Ferguson-Smith and Bourc’his. eLife 2018;7:e42368. DOI: https://doi.org/10.7554/eLife.42368 2 of 5 Feature article 2018 Gairdner Awards The discovery and importance of genomic imprinting Variations of imprinting in space and time Though we still do not understand Many genome-wide screens have been devel- oped to identify new imprinted loci but the gen- the evolutionary processes that eral conclusion is that all the canonical ICRs – have led to the emergence of that is, those with parent-specific DNA methyla- tion patterns that are maintained in a life-long genomic imprinting in mammals, its and tissue-wide manner – have probably been interrogation over the years has uncovered (Xie et al., 2012). Less robust ICRs have been detected, whereby parent-specific revealed a wealth of epigenetic DNA methylation patterns are confined
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