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Genomic Imprinting: Employing and Avoiding Epigenetic Processes

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Genomic Imprinting: Employing and Avoiding Epigenetic Processes Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Genomic imprinting: employing and avoiding epigenetic processes Marisa S. Bartolomei1 Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA Genomic imprinting refers to an epigenetic mark that genomic_imprinting for a full list), with the imprinting distinguishes parental alleles and results in a monoallelic, of many of these genes conserved in humans (http:// parental-specific expression pattern in mammals. Few www.otago.ac.nz/IGC). Although additional genes and phenomena in nature depend more on epigenetic mech- transcripts may be discovered using more modern se- anisms while at the same time evading them. The alleles quence analysis of transcriptomes, it is notable that the of imprinted genes are marked epigenetically at discrete first few published studies of this nature reported only elements termed imprinting control regions (ICRs) with a small number of novel imprinted genes, suggesting that their parental origin in gametes through the use of DNA many new widely expressed imprinted genes are not methylation, at the very least. Imprinted gene expression likely to be identified (Babak et al. 2008; Wang et al. is subsequently maintained using noncoding RNAs, 2008). Nevertheless, more detailed, allele-specific tran- histone modifications, insulators, and higher-order chro- scriptome analyses of purified cell populations should add matin structure. Avoidance is manifest when imprinted to the growing list of tissue-specific imprinted genes. genes evade the genome-wide reprogramming that oc- Imprinted genes have a variety of functions; many curs after fertilization and remain marked with their imprinted genes are important for fetal and placental parental origin. This review summarizes what is known growth and development, whereas others are involved in about the establishment and maintenance of imprinting postnatal behavior. Imprinted genes are also located marks and discusses the mechanisms of imprinting in throughout the genome, including on the X chromosome. clusters. Additionally, the evolution of imprinted gene Some imprinted genes currently map as singletons or in clusters is described. While considerable information discrete pairs, but most imprinted genes reside in ;1-Mb regarding epigenetic control of imprinting has been clusters (O’Neill 2005). These larger clusters usually obtained recently, much remains to be learned. contain at least one noncoding RNA (ncRNA), which is often >100 kb in length, and maternally and paternally Mammals possess a small number of genes subject to an expressed genes (Fig. 1). Also present within each cluster unusual form of gene regulation, termed genomic im- is an imprinting control region (ICR; alternatively called printing (Barlow and Bartolomei 2007). Genomic imprint- imprinting control element [ICE] or differentially meth- ing, which results in the parental-specific expression of ylated domain [DMD]). The region, typically a few kilo- these genes, is proposed to be the major block to parthe- base pairs in length, exhibits parental allele-specific DNA nogenesis in mammals (Kono et al. 2004). Genomic methylation and post-translational histone modifica- imprinting also subjects mammals to a greater genomic tions. Furthermore, when the ICR is deleted, loss of risk because a mutation in one allele (either genetic or imprinted gene expression is observed for the linked epigenetic) can result in the absence of one or more gene genes (Wutz et al. 1997; Thorvaldsen et al. 1998; Yang products, thereby leading to a number of well-known et al. 1998; Fitzpatrick et al. 2002; Lin et al. 2003; imprinting disorders, including Beckwith-Wiedemann Williamson et al. 2006). This review describes the prop- syndrome, Silver-Russell syndrome, Prader-Willi syndrome, erties of this unusual form of gene expression, the two and Angelman syndrome (Horsthemke and Wagstaff main hypothesized mechanisms of imprinted gene ex- 2008; Ideraabdullah et al. 2008). pression, and studies that address the evolution of At this time, there are ;100 imprinted genes identified imprinted gene loci. in the mouse (see http://www.har.mrc.ac.uk/research/ Unusual properties of imprinted genes Imprinted genes display properties that separate them [Keywords: DNA methylation; epigenetics; genomic imprinting; insu- from the majority of the mammalian genome. First, the lators; ncRNA] alleles of these genes must be differentially modified, or 1Correspondence. E-MAIL [email protected]; FAX (215) 573-6434. epigenetically marked, with their parental origin so that Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1841409. appropriate patterns of expression are assumed in the 2124 GENES & DEVELOPMENT 23:2124–2133 Ó 2009 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/09; www.genesdev.org Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Genomic imprinting in mammals Figure 1. Components of an imprinted gene cluster. The maternal (top) and paternal (bottom) alleles of an imprinted gene cluster are depicted. Imprinted gene clusters contain maternally expressed (pink-filled boxes), paternally expressed (blue-filled boxes), and biallelically expressed genes (i.e., nonimprinted genes, green-filled boxes). These nonimprinted genes can be found in the middle of a cluster surrounded by imprinted genes. The ICR (yellow) controls imprinting of multiple genes in the region; deletion of this differentially methylated element results in loss of im- printing of the linked genes. Many imprinted clusters also contain additional DMRs (orange) that acquire DNA methylation after the preimplantation stage. Not depicted here are long ncRNAs and insulators, which have an essential role in imprinted clusters. soma. It has long been hypothesized that this marking required to assay allele-specific post-translational histone occurs in the germline, because this is the time when modifications and higher-order chromatin structure parental genomes are in separate compartments and can makes it difficult to assess the role of these modifications be differentially modified. Second, the germline marks in germ cells and early embryos. Thus, much attention must be maintained after fertilization when the vast has focused on acquisition and maintenance of DNA majority of the genome is being reprogrammed. Here, methylation. Curiously, most ICRs are methylated on the DNA methylation and post-translational histone modifi- maternal allele, and this methylation is established dur- cations are erased and reset during the process in which ing the oocyte growth phase prior to ovulation (Lucifero pluripotent cells of the preimplantation embryo give rise et al. 2002). In contrast, the three paternally methyl- to cells of various fates, while imprints are maintained ated ICRs (H19/Igf2, Dlk1/Dio3, and Rasgrf1) are meth- (Morgan et al. 2005). DNA appears actively demethylated ylated in gonocytes during the period between mitotic on the paternal genome within hours of fertilization and arrest and birth (Davis et al. 1999; Li et al. 2004). The use is subsequently passively demethylated on the maternal of conditional deletion alleles of the de novo family of genome (Rougier et al. 1998; Mayer et al. 2000; Oswald DNA methyltransferase proteins has shown that all of et al. 2000). The precise mechanism of this demethylation the ICRs tested to date, with one exception, use the de has been called into question with the recent description novo DNA methyltransferase DNMT3A and its stimula- of 5-hydroxymethylcytosine in mammals and the iden- tory protein, DNMT3L, to confer DNA methylation on tification of TET1, which catalyzes the conversion of the ICRs in the respective germ cells (Bourc’his et al. 5-methylcytosine to this modified base (Kriaucionis and 2001; Hata et al. 2002; Bourc’his and Bestor 2004; Kaneda Heintz 2009; Tahiliani et al. 2009). However, regardless of et al. 2004). The exception is the Rasgrf1 ICR, which is the mechanism, imprinted genes are uniquely immune to methylated in male germ cells and uses the de novo DNA the demethylation process during preimplantation de- methyltransferase DNMT3B. The reason for this differ- velopment. Thus, an important question remains as to ence is unclear, but is most likely due to the fact that the how imprints are protected from genome-wide demeth- enzyme predominantly methylates repetitive DNA and ylation. Finally, imprints are largely maintained in the the Rasgrf1 ICR and surrounding sequences are highly soma, although tissue-specific imprinting is frequently repetitive. In summary, we know (1) the sequences that observed, and are subsequently erased during germ are methylated in the germ cells (ICRs), (2) when the cell development. In the germline, however, erasure of marks are put on the ICRs, and (3) the enzymes that imprints is not unique, as most of the genome is repro- confer the marks. However, it is still unclear how the grammed at this time. More specifically, DNA demeth- epigenetic machinery recognizes ICR sequences. One ylation, which serves as a proxy for erasure of genomic clue comes from the structural analysis of the complexed imprints, occurs concomitantly with demethylation of C-terminal domains of DNMT3A and DNMT3L, which other parts of the genome (Hajkova et al. 2002). was obtained by X-ray crystallography (Jia et al. 2007). A tetrameric complex consisting
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