Widespread occurrence of antisense transcription in the human genome

Yelin, Rodrigo; Dahary, Dvir; Sorek, Rotem; Levanon, Erez Y.; Goldstein, Orly; Shoshan, Avi; Diber, Alex; Biton, Sharon; Tamir, Yael; Khosravi, Rami; Nemzer, Sergey; Pinner, Elhanan; Walach, Shira; Bernstein, Jeanne; Savitsky, Kinneret; Rotman, Galit

doi:10.1038/nbt808

Cited by 595 publications

(484 citation statements)

References 29 publications

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“…They are far more frequent than previously anticipated 5,48 . A recent computational survey estimated that there are ∼1,600 human SATs (∼3,200 transcriptional units) 5 . Similar results were obtained from an analysis of the mouse FANTOM2 clone set.…”

Section: Rna-directed Dna Read-outmentioning

confidence: 75%

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: 75%

The four Rs of RNA-directed evolution

Herbert

2003

Nat Genet

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“…Recent progress in transcriptome analysis has revealed that a large proportion of the genome can be transcribed from both strands, producing sense and antisense transcripts (Carninci et al, 2005;Kiyosawa et al, 2003;Yelin et al, 2003). The available evidence suggests that certain classes of RNA are causally involved in not only gene regulation but also higher order chromatin structure in various organisms (Bernstein and Allis, 2005).…”

Section: Introductionmentioning

confidence: 99%

Tsixdefective in splicing is competent to establishXistsilencing

2006

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Dosage differences of X-linked genes between male and female mammals are compensated for by a mechanism known as Xinactivation, and the noncoding Xist gene plays a crucial role in this process. The expression of Xist is regulated in cis by its noncoding antisense gene, Tsix, whose transcripts (though a fraction of them stay unspliced), are processed like common proteincoding RNAs. It has been suggested that certain classes of sense-antisense pairs of RNA are causally involved in not only gene regulation but also higher order chromatin structure in various organisms. In fact, recent studies demonstrated that Tsix modulates Xist expression through modification of the chromatin structure. It is still unknown, however, whether the RNA product is important for the function of Tsix or whether the antisense transcription is sufficient. To obtain insight into this issue, we eliminated the splicing products of Tsix in the mouse and explored the effects of this elimination on Tsix-mediated Xist silencing. To our surprise, the Xist locus was stably repressed on the X carrying the splicing-defective Tsix allele. Moreover, the repressive chromatin configuration was properly established at the Xist locus. These unexpected results indicate that the splicing products are dispensable for Tsix-mediated Xist silencing.

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“…Similarly, public database analyses suggested the presence of approximately 1,600 sense-antisense gene pairs in the human genome (Yelin et al, 2003). These studies concluded that the occurrence of loci transcribed from both DNA strands in the mammalian genome is a common phenomenon; however, insights about their putative functional relevance are limited.…”

Section: Resultsmentioning

confidence: 99%

Expression of Six3 Opposite Strand (Six3OS) during mouse embryonic development

Geng

Lavado

Lagutin

et al. 2007

Gene Expression Patterns

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Recently, sequence analyses have identified a large number of opposite strands transcripts in the vertebrate genome. Although the transcripts appear to be spliced and polyadenylated, many of them are predicted to represent noncoding RNAs. High levels of noncoding transcripts of the Six3 opposite strand (Six3OS) were recently identified in the embryonic and postnatal retina of the mouse. In this study, we expanded those initial expression analyses, elucidated in detail the developmental expression profile of mouse Six3OS in the brain and visual system, and compared it with that of Six3. Our results show that Six3OS expression overlaps extensively with that of Six3 and is not altered in Six3-null embryos.

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Widespread occurrence of antisense transcription in the human genome

Cited by 595 publications

References 29 publications

The four Rs of RNA-directed evolution

The four Rs of RNA-directed evolution

Tsixdefective in splicing is competent to establishXistsilencing

Expression of Six3 Opposite Strand (Six3OS) during mouse embryonic development

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