Noncoding RNA Genes in Dosage Compensation and Imprinting

Abstract

Alleles silenced via imprinting are not thought to be packaged in densely compacted heterochromatin, but several imprinted genes have oppositely imprinted noncoding RNA partners nearby on the chromosome. Maternal expression of the Igf2r gene is reminiscent of the Xist/Tsix locus in that imprinting is tied to antisense transcription on the paternal chromosome (Wutz et al. 1997xWutz, A, Smrzka, O.W, Schweifer, N, Schellander, K, Wagner, E.F, and Barlow, D.P. Nature. 1997; 389: 745–749Crossref | PubMed | Scopus (421)See all ReferencesWutz et al. 1997) (Figure 1CFigure 1C). Perhaps the most intensively studied example of imprinting is the paternally expressed Ins2 Igf2 gene cluster that is linked to the maternally expressed H19 gene (Tilghman 1999xTilghman, S.M. Cell. 1999; 96: 185–193Abstract | Full Text | Full Text PDF | PubMed | Scopus (385)See all ReferencesTilghman 1999) (Figure 2AFigure 2A). Although no function has been found for the noncoding H19 RNA, it is conserved and abundantly expressed. Moreover, the Dlk1/Gtl2 locus was recently found to have a nearly identical arrangement of a paternally imprinted protein coding gene adjacent to a maternally imprinted noncoding RNA, suggesting some type of selection for these unusual RNAs (Schmidt et al. 2000xSchmidt, J.V, Matteson, P.G, Jones, B.K, Guan, X.-J, and Tilghman, S.M. Genes Dev. 2000; 14: 1997–2002PubMedSee all ReferencesSchmidt et al. 2000) (Figure 2BFigure 2B).Figure 2Reciprocal Imprinting of Adjacent Protein-Coding and Noncoding RNA Genes(A) Reciprocal imprinting is observed at the Igf2 locus where a single enhancer drives expression of either Ins2 and Igf2 from the paternal homolog, or noncoding H19 RNA from the maternal chromosome. The imprinting control region (ICR) contains CpG-rich sequences that serve as the binding site for the chromatin insulator CTCF. When CTCF occupies the ICR, the enhancer cannot act on distal genes, and H19 is transcribed. Paternal methylation of the ICR prevents CTCF binding allowing the enhancer to act on the Igf2 and Ins2 genes (5xHark, A.T, Schoenherr, C.J, Katz, D.J, Ingram, R.S, Levorse, J.M, and Tilghman, S.M. Nature. 2000; 405: 486–489Crossref | PubMed | Scopus (946)See all References, 3xBell, A.C and Felsenfeld, G. Nature. 2000; 405: 482–485Crossref | PubMed | Scopus (1003)See all References).(B) The paternally imprinted Dlk1 gene is upstream of a maternally imprinted Gtl2 gene, which makes a noncoding RNA. As with the Igf2/H19 locus, a differentially methylated CpG-rich region (filled circle) lies upstream on the noncoding RNA gene.View Large Image | View Hi-Res Image | Download PowerPoint SlideAs unconventional RNAs are being encountered in novel epigenetic regulatory mechanisms, one striking feature is that the site of synthesis is critical to function. In both mammals and flies, moving the Xist or roX genes from the X to autosomes redirects dosage compensation to the new sites of insertion. Antisense Tsix expression from one homolog cannot regulate the Xist allele from the other homolog, demonstrating exclusive cis activity. The same appears to be true within the Igf2r locus. Is it possible that RNA is a common epigenetic regulator? By analogy to the RNAs discovered so far, noncoding RNAs could function by repackaging a local segment of chromatin, or by capturing a complementary mRNA, or they could simply be by-products from some type of mutually exclusive action of linked promoters.‡E-mail: rkelley@bcm.tmc.edu (R. L. K.), mkuroda@bcm.tmc.edu (M. I. K.)