The Air noncoding RNA: an imprinted cis-silencing transcript

Autor: Florian M. Pauler, O. Smrzka, G. Braidotti, Stefan H. Stricker, Tuncay Baubec, Iveta Yotova, Denise P. Barlow, Christine I.M. Seidl
Rok vydání: 2005
Předmět:
Zdroj: Cold Spring Harbor symposia on quantitative biology. 69
ISSN: 0091-7451
Popis: Genomic imprinting is briefly defined as parental-specific gene expression. It is a feature of organisms with diploid cells that have inherited a complete haploid chromosome set from two parents and, thereby, have a maternal and paternal allele for each autosomal gene. Diploid cells would normally be expected to express both parental alleles equally but imprinted genes are different, because they acquire an epigenetic mark from one parental gamete that results in repression on one parental allele and expression from the other. Genomic imprinting uses an epigenetic mechanism (i.e., a reversible modification to DNA or chromatin) to regulate gene expression in cis that is assumed to be at the level of transcriptional, but this is not often tested. Genomic imprinting has been so far identified in very diverse organisms: in angiosperm plants, in two types of invertebrates (sciarid flies, mealybugs), and lastly in mammals that have live-born young (marsupial and placental mammals) (Goday and Esteban 2001; Killian et al. 2001; Baroux et al. 2002). These diverse organisms lack a contemporary common ancestor that also shows imprinted gene expression, and this allows the possibility that imprinting arose independently at least three times in distantly related organisms. If this is so, the imprinting mechanism in these diverse organisms is less likely to share common features. The function of genomic imprinting is beginning to be understood following the functional analysis of a large number of imprinted genes in mice (see listing at http://www.mgu.har.mrc.ac.uk/research/imprinting/function.html). There is now sufficient information to suggest that genomic imprinting arose in mammals as a consequence of one parent carrying the total burden of provision for an embryo that carries the genomes of two parents. Thus, imprinted genes in mammals are able to influence embryonic growth in such a manner that imprinted growth suppressor genes are always maternally expressed, while imprinted growth promoter genes are always paternally expressed (Wilkins and Haig 2003). The reason imprinted genes exist in angiosperm plants is not yet clear, although it has been suggested that angiosperm plants resemble mammals because biparental seeds are also grown by one parent (Moore and Haig 1991). The two invertebrates with genomic imprinting appear to use this as a sex-determining mechanism, such that males are produced by inactivating the paternal genome in diploid offspring (Goday and Esteban 2001; Bongiorni and Prantera 2003). The Harwell Mammalian Genetics Unit has for many years maintained a complete list of the known imprinted mouse genes and also lists mutant phenotypes for those imprinted genes so far analyzed (Beechey et al. 2003). Table 1 was drawn from this information and lists the 70 known imprinted genes by chromosomal subregions (note many imprinted genes have alternative names and these are listed on http://www.mgu.har.mrc.ac.uk/research/imprinting/). The imprinted genes are separated in this list according to parental expression and whether they are coding or noncoding. Several features of mammalian imprinted genes become apparent from this list. Table 1 Imprinted Genes Are Mainly Organized into Clusters Only 12 of 19 mouse autosomal chromosomes carry imprinted genes; however, four chromosomes (2, 6, 7, and 10) have multiple subregions carrying imprinted genes. Imprinted genes are often clustered. There are 18 regions with imprinted genes and 12 have clusters containing between 2 and 9 imprinted genes. Some genes inside the cluster escape imprinting. Many imprinted genes are noncoding RNAs (ncRNAs) that show three types of pattern: antisense to one imprinted gene and expressed from the opposite parental allele (e.g., proximal 17: Igf2r/Air; distal 7a: Kcnq1/Lit1); antisense to one imprinted gene and expressed from the same chromosome (distal 7b: Igf2/Igf2as; central 7: Zfp127/Zfp127as); and sense to one imprinted gene and expressed from the opposite parental allele (distal 7b: Igf2/H19; distal 12: Dlk1/Gtl2). There are approximately equal numbers of maternally and paternally expressed coding (mRNA) genes, but there are less maternally expressed ncRNAs than paternally expressed ncRNAs (note that the multiple ncRNAs from central 7 and distal 12 may arise from a single long processed ncRNA). Reciprocal parental-specific expression between protein-coding genes and an ncRNA is often observed. Two patterns are seen: A simple type where all the protein-coding genes are expressed by one parental chromosome and the ncRNA from the other (e.g., distal 7a, distal 7b, distal 12, proximal 17), and a complex type where multiple protein coding genes are maternally or paternally expressed while the noncoding RNA is expressed from one parental chromosome (e.g., distal 2, subproximal 6, central 7). The observation that imprinted genes exist in clusters suggests that mechanisms to control imprinted expression act on the chromosomal domain rather than on individual genes (Reik and Walter 2001; Verona et al. 2003). If imprinting control mechanisms are specific to a domain this could explain why moving imprinted genes outside their endogenous locus on transgenes causes them to lose imprinted expression (Lee et al. 1993; Sleutels and Barlow 2001). The observation of reciprocal imprinted expression between the clustered protein-coding genes and the noncoding RNA is fascinating and naturally suggests a link between expression of a noncoding RNA and cis-induced silencing of the protein coding RNA. The data that tests the significance of this association between ncRNAs and cis-induced silencing is only beginning to appear. There are, however, two significant results so far (for review, see Verona et al. 2003). First, there was a clear demonstration that the H19 ncRNA plays no role in silencing the reciprocally expressed Ins2/Igf2 genes in cis (Jones et al. 1998; Schmidt et al. 1999). Instead a DNA sequence functions as a methyl-sensitive insulator that, when methylated, allows expression of Igf2 and, when unmethlyated, allows expression of H19 (Bell and Felsenfeld 2000; Hark et al. 2000). The second result, and the topic of the remainder of this review, was the demonstration that the Air ncRNA plays a direct role in silencing a cluster of three genes spanning 300 kilobases (kb) in cis (Rougeulle and Heard 2002; Sleutels et al. 2002).
Databáze: OpenAIRE
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