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Faghihi, Mohammad Ali; Wahlestedt, Claes

doi:10.1186/gb-2006-7-5-r38

Cited by 53 publications

(18 citation statements)

References 28 publications

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“…Genic endo-siRNAs have been documented in several systems, predominantly in C. elegans , Drosophila and also in mouse [18,37-40]. However, in mammalian systems, the link between convergent transcription and RNA interference is controversial [41]. Our results confirm the existence of endo-siRNAs in human cells and the fact that 53% of these derive from SA loci provides circumstantial evidence that sense/antisense transcription may be involved.…”

Section: Discussionsupporting

confidence: 78%

Contribution of natural antisense transcription to an endogenous siRNA signature in human cells

et al. 2014

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BackgroundEukaryotic cells express a complex layer of noncoding RNAs. An intriguing family of regulatory RNAs includes transcripts from the opposite strand of protein coding genes, so called natural antisense transcripts (NATs). Here, we test the hypothesis that antisense transcription triggers RNA interference and gives rise to endogenous short RNAs (endo-siRNAs).ResultsWe used cloned human embryonic kidney cells (HEK293) followed by short RNAseq to investigate the small genic RNA transcriptome. 378 genes gave rise to short RNA reads that mapped to exons of RefSeq genes. The length profile of short RNAs showed a broad peak of 20-24 nucleotides, indicative of endo-siRNAs. Collapsed reads mapped predominantly to the first and the last exon of genes (74%). RNAs reads were intersected with sequences occupied by RNAPII or bound to Argonaute (AGO1 by crosslinking, ligation, and sequencing of hybrids, CLASH). In the first exon, 94% of the reads correlated with RNAPII occupancy with an average density of 130 (relative units); this decreased to 65%/20 in middle exons and 54%/12 in the last exon. CLASH reads mapping to multi-exon genes showed little distribution bias with an average of about 5 CLASH reads overlapping with 60% of the endo-siRNA reads. However, endo-siRNAs (21-25 nt) intersecting with CLASH reads were enriched at the 5′end and decreased towards the 3′end.We then investigated the 378 genes with particular focus on features indicative for short RNA production; however, found that endo-siRNA numbers did not correlate with gene structures that favor convergent transcription. In contrast, our gene set was found notably over-represented in the NATsDB sense/antisense group as compared to non-overlapping and non-bidirectional groups. Moreover, read counts showed no correlation with the steady-state levels of the related mRNAs and the pattern of endo-siRNAs proved reproducible after an induced mutagenic insult.ConclusionsOur results suggest that antisense transcripts contribute to low levels of endo-siRNAs in fully differentiated human cells. A characteristic endo-siRNA footprint is being produced at sites of RNAPII transcription which is also related to AGO1. This endo-siRNA signature represents an intriguing finding and its reproducibility suggests that the production of endo-siRNAs is a regulated process with potential homoeostatic impact.

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Section: Discussionsupporting

confidence: 78%

Contribution of natural antisense transcription to an endogenous siRNA signature in human cells

et al. 2014

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“…However, siRNAs generated from bidirectional transcription of the 5Ј-UTR of L1 retrotransposons have been identified in human cells that play a role in suppressing retrotransposition (70). Others have argued that the RNA interference pathway is not importantly involved in the regulation of natural S/AS genes (71). This recent work demonstrated that sense and antisense RNAs are often present in different subcellular compartments and do not physically interact in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase

Fish

Matouk

Yeboah

et al. 2007

Journal of Biological Chemistry

132

120

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The destabilization of endothelial nitric-oxide synthase (eNOS) mRNA in hypoxic endothelial cells may be important in the etiology of vascular diseases, such as pulmonary hypertension. Recently, an overlapping antisense transcript to eNOS/NOS3 was implicated in the post-transcriptional regulation of eNOS. We demonstrate here that expression of sONE, also known as eNOS antisense (NOS3AS) or autophagy 9-like 2 (APG9L2), is robustly induced by hypoxia or functional deficiency of von Hippel-Lindau protein. sONE is also up-regulated in the aortas of hypoxic rats. In hypoxic endothelial cells, sONE expression negatively correlates with eNOS expression. Blocking the hypoxic induction of sONE by RNA interference attenuates the fall in both eNOS RNA and protein. We provide evidence that the induction of sONE primarily involves transcript stabilization rather than increased transcriptional activity and is von Hippel-Lindau-but not hypoxia-inducible factor 2␣-dependent. We also demonstrate that sONE transcripts are enriched in the nucleus of normoxic cells and that hypoxia promotes an increase in the level of cytoplasmic and polyribosome-associated, sONE mRNA. The finding that eNOS expression can be regulated by an overlapping cis-antisense transcript in a stimulus-dependent fashion provides evidence that sense/antisense interactions may play a previously unappreciated role in vascular disease pathogenesis.

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“…It was estimated that about one third of protein-coding genes process NATs 21 . Interestingly, studies showed that the NAT regulatory mechanism is more likely a consequence of epigenetic modulation such as DNA methylation induced by NAT interaction with DNA methyltransferases and modification of chromatin structure by recruiting histone-modifying enzymes to the genomic locus, rather than the previously presumed direct degradation of the sense transcript through siRNA-like degradation mechanism for complementary sequences 21, 105, 114 .…”

Section: Involvement Of Lncrnas In Cancer and Therapeutic Implicationsmentioning

confidence: 99%

MicroRNAs and other non-coding RNAs as targets for anticancer drug development

Ling

Fabbri

Calin

2013

Nat Rev Drug Discov

1,283

991

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With the first cancer-targeted microRNA drug, MRX34, a liposome-based miR-34 mimic, entering phase I clinical trial in patients with advanced hepatocellular carcinoma in April 2013, miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although to date the most studied non-coding RNAs (ncRNAs) are miRNAs, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges.

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Untitled

Cited by 53 publications

References 28 publications

Contribution of natural antisense transcription to an endogenous siRNA signature in human cells

Contribution of natural antisense transcription to an endogenous siRNA signature in human cells

Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase

MicroRNAs and other non-coding RNAs as targets for anticancer drug development

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