The non-coding Air RNA is required for silencing autosomal imprinted genes

Sleutels, Frank; Zwart, Ronald; Barlow, Denise P.

doi:10.1038/415810a

Cited by 973 publications

(818 citation statements)

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“…When both transcriptional units are active, formation of dsRNA occurs by default, leading to histone modification and TGS: SATs effectively cancel each other, relaxing the need for stringent regulation of promoter engagement by transcription factors. An example is the imprinting of the gene Igf2r in mice 50 . Expression of Igfr2 depends on whether the locus is inherited from either the mother or the father.…”

Section: Rna-directed Dna Read-outmentioning

confidence: 99%

“…Expression from the paternal chromosome is prevented by an antisense transcript produced by the non-protein coding gene Air. Net expression of Igfr2 occurs only from the maternal chromosome, as methylation of the maternal Air gene promoter prevents production of an antisense transcript 50 . This mechanism might be quite general.…”

Section: Rna-directed Dna Read-outmentioning

confidence: 99%

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The four Rs of RNA-directed evolution

Herbert

2003

Nat Genet

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The read-out of genetic information in eukaryotes is not only more complex than previously realized, but also more dynamic. Much of the information is 'soft-wired' , with extensive RNA processing necessary to generate phenotypes 10 . A subset of the RNA, referred to here as coRNA ( Fig. 1), coordinates the read-out of genetic information and reconciles regulatory inputs. For each cell type, the sum of these interactions defines a distinct RNA profile or ribotype 10 . RNA-based processes also facilitate replication of ribotypes in subsequent generations. The flexibility of these programs allows soft-wired organisms to evolve in a more rapid and dynamic way than 'hard-wired' organisms constrained by DNA mutation 10 . Together, the actions of reading, 'riting, 'rithmetic and replication constitute the four Rs of RNA-directed evolution. Here, we describe roles for coRNAs and SATs (Fig. 2) in these events. RNA-directed RNA readoutRNA coregulates the sequence-specific read-out of genetic information from RNA by targeting the evolutionarily conserved machinery of RNA interference (RNAi) 11 and translational repression. RNAi leading to post-transcriptional gene silencing (PTGS) is induced by doublestranded RNA (dsRNA) arising from infection by dsRNA viruses, senseantisense transcription pairs, transcription of inverted repeats and delivery of dsRNAs manufactured in vitro 12 . Both endogenous and exogenous dsRNAs are processed cytoplasmically by RNase III dicer paralogs into small interfering RNAs (siRNAs) that are 21-25 bases long 12,13 . These siRNAs are incorporated into an RNA-induced silencing complex (RISC) that targets any RNA with a sequence complementary to the siRNA 12,14 . The target RNA is cleaved by RISC, which has endonucleolytic and presumed exonucleolytic activity 12,15 . Each cycle results in the destruction of the target RNA and the regeneration of an active RISC 16,17 .In Neurospora crassa 18,19 , plants 20 , Schizosaccharomyces pombe 21 and Caenorhabditis elegans 22 , but not in flies, humans or mouse oocyctes 18,19,23,24 , PTGS can also be initiated by an RNA-dependent RNA polymerase (RdRP) that synthesizes complementary RNA from highly expressed transcripts to generate dsRNA. This process can spread from the 3´ to the 5´ end of the mRNA, leading to progressive silencing of a gene and other mRNAs with exons in common (transitive RNAi) 18,22 . From the evolutionary viewpoint, transitive RNAi favors the generation of new phenotypes, as related genes in species with polyploid genomes will escape cosuppression by sequence divergence, resulting in altered function or expression.The number of dicer paralogs also differs between species. Arabidopsis, which has at least four dicer family members, seems to use different enzymes to defend against viruses and to process endogenously produced dsRNA 13,25 . In humans, mice and worms, there is only one dicer ortholog, suggesting that any pathway-specific functions are guided by ancillary regulatory proteins associated with RISC. These ancillary proteins include me...

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Section: Rna-directed Dna Read-outmentioning

confidence: 99%

Section: Rna-directed Dna Read-outmentioning

confidence: 99%

The four Rs of RNA-directed evolution

Herbert

2003

Nat Genet

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“…On the maternal chromosome, DNA methylation prevents transcription of Air and Kcnq1ot1, allowing clusters of imprinted genes to be expressed (Stoger et al, 1993;Engemann et al, 2000). On the paternal chromosome, all three coding genes in the Igf2r cluster, Igf2r, slc22a2, and slc22a3, are silenced by Air, even though it is only antisense to Igf2r (Sleutels et al, 2002). How Air silences Igf2r cluster remains to be determined, but regulatory mechanisms behind the silencing of Kcnq1 may yield some clues.…”

Section: Genomic Imprintingmentioning

confidence: 99%

Epigenetics in development

Kiefer

2007

Developmental Dynamics

236

144

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It has become increasingly evident in recent years that development is under epigenetic control. Epigenetics is the study of heritable changes in gene function that occur independently of alterations to primary DNA sequence. The best-studied epigenetic modifications are DNA methylation, and changes in chromatin structure by histone modifications, and histone exchange. An exciting, new chapter in the field is the finding that long-distance chromosomal interactions also modify gene expression. Epigenetic modifications are key regulators of important developmental events, including X-inactivation, genomic imprinting, patterning by Hox genes and neuronal development. This primer covers these aspects of epigenetics in brief, and features an interview with two epigenetic scientists. Developmental Dynamics 236: 1144 -1156, 2007.

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“…(2) Noncoding RNAs act in cis to regulate gene expression. Sleutels et al [2002] showed that, in the mouse Igf2r imprinted cluster, truncation of the noncoding Air RNA that is transcribed from its promoter in the IC causes loss of imprinting for all genes in the cluster. However, in the PWS/AS region, a deletion extending from Snrpn intron 1 to Ube3a intron 1 removes almost all of the paternally-expressed region downstream from the PWS-IC, but paternal deletion of this region has no effect on imprinted expression of Ndn [Tsai et al, 1999].…”

Section: Summary Synthesis and Extension To Other Imprinted Regionsmentioning

confidence: 99%

Imprinting centers, chromatin structure, and disease

Soejima

Wagstaff

2005

J of Cellular Biochemistry

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Two regions that best exemplify the role of genetic imprinting in human disease are the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region in 15q11-q13 and the Beckwith-Wiedemann syndrome (BWS) region in 11p15.5. In both regions, cis-acting sequences known as imprinting centers (ICs) regulate parent-specific gene expression bidirectionally over long distances. ICs for both regions are subject to parent-specific epigenetic marking by covalent modification of DNA and histones. In this review, we summarize our current understanding of IC function and IC modification in these two regions. J. Cell. Biochem. 95: 226-233, 2005. ß 2005 Wiley-Liss, Inc.

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The non-coding Air RNA is required for silencing autosomal imprinted genes

Cited by 973 publications

References 24 publications

The four Rs of RNA-directed evolution

The four Rs of RNA-directed evolution

Epigenetics in development

Imprinting centers, chromatin structure, and disease

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