Extensive relationship between antisense transcription and alternative splicing in the human genome

Morrissy, A. Sorana; Griffith, Malachi; Marra, Marco A.

doi:10.1101/gr.113431.110

Cited by 72 publications

(67 citation statements)

References 59 publications

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“…Early observations that the ratio of splice isoforms for a number of mRNAs can be influenced by expression of overlapping antisense transcripts, and that the latter can form RNA duplexes with the mRNAs opposite them in vivo and/or inhibit splicing in vitro, led to speculation that NAT-mediated alternative splicing may be a common method of post-transcriptional regulation (Munroe 1988;Krystal et al 1990;Khochbin et al 1992;Yan et al 2005;Beltran et al 2008;Annilo et al 2009). More recent genome-wide analysis has indeed revealed correlations between overlapping SAS pairs and alternative splicing (namely, enrichment of alternative exons in overlapping regions and increased number of alternative splice isoforms) (Morrissy et al 2011). One notable case is the a-thyroid hormone receptor gene erbAa, which produces two mRNA isoforms and has a downstream, translated antisense transcript called RevErb (thus, not a lncRNA per se) whose 39-untranslated region (UTR) overlaps the last splice acceptor site of the long erbAa isoform (Lazar et al 1989).…”

Section: Transcript or Act Of Transcription?mentioning

confidence: 99%

Long Noncoding RNAs: Past, Present, and Future

2013

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Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years as a potentially new and crucial layer of biological regulation. lncRNAs of all kinds have been implicated in a range of developmental processes and diseases, but knowledge of the mechanisms by which they act is still surprisingly limited, and claims that almost the entirety of the mammalian genome is transcribed into functional noncoding transcripts remain controversial. At the same time, a small number of well-studied lncRNAs have given us important clues about the biology of these molecules, and a few key functional and mechanistic themes have begun to emerge, although the robustness of these models and classification schemes remains to be seen. Here, we review the current state of knowledge of the lncRNA field, discussing what is known about the genomic contexts, biological functions, and mechanisms of action of lncRNAs. We also reflect on how the recent interest in lncRNAs is deeply rooted in biology's longstanding concern with the evolution and function of genomes.T HE past several years have witnessed a steep rise of interest in the study of lncRNAs. Almost on a weekly basis, it seems that a new lncRNA is found to be up-or downregulated in a particular disease, or a new class of noncoding transcripts is uncovered by a transcriptomic study, or a new article heralds a paradigm shift that lncRNAs will bring to our understanding of biology. Without a doubt, the advent of sensitive, high-throughput genomic technologies such as microarrays and next-generation sequencing (NGS) has resulted in an unprecedented ability to detect novel transcripts, the vast majority of which seem not to be derived from annotated protein-coding genes. Despite this explosion of data, however, surprisingly little is known about how lncRNAs function, how many different types of lncRNAs exist, or even whether most of them carry biological significance.In this review, we focus on recently discovered lncRNAs of .200 nt, place these new discoveries in historical context, and outline areas where additional work is needed. The review does not cover "classic" ncRNAs such as ribosomal (r) RNAs, ribozymes, transfer (t)RNAs, small nuclear (sn)RNAs, small nucleolar (sno)RNAs, and telomere-associated RNAs (TERC, TERRA); nor does it cover small ncRNAs such as microRNAs (miRNAs), endogenous small interfering (endo-si)RNAs that participate in RNA interference (RNAi), and Piwi-associated (pi)RNAs. We refer readers to the many

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Section: Transcript or Act Of Transcription?mentioning

confidence: 99%

Long Noncoding RNAs: Past, Present, and Future

2013

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“…cis-NAT pairs have been implicated in the process of mRNA splicing in both plants and mammals (Chen et al 2005;Jen et al 2005;Morrissy et al 2011). In Arabidopsis, genes with multiple exons are more likely to be found in cis-NAT pairs than randomly selected gene pairs.…”

Section: Genomic Evidence Supports the Set Of Novel Cis-nat Pairsmentioning

confidence: 99%

“…Although sequencing of cDNA/EST libraries ( Jen et al 2005;Wang et al 2005) and microarray experiments (Ge et al 2008;Morrissy et al 2011) have provided preliminary genome-wide assessments of cis-NATs (Henz et al 2007;Jin et al 2008;Chen et al 2012), results from these early studies are less than ideal (Weber et al 2007). In recent years, the advent of high-throughput sequencing has provided the opportunity to systematically characterize the transcriptome at higher coverage and better accuracy than conventional approaches (Mortazavi et al 2008).…”

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confidence: 99%

Integrated detection of natural antisense transcripts using strand-specific RNA sequencing data

Liberman

Mukherjee

et al. 2013

Genome Res.

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Pairs of RNA molecules transcribed from partially or entirely complementary loci are called cis-natural antisense transcripts (cis-NATs), and they play key roles in the regulation of gene expression in many organisms. A promising experimental tool for profiling sense and antisense transcription is strand-specific RNA sequencing (ssRNA-seq). To identify cisNATs using ssRNA-seq, we developed a new computational method based on a model comparison framework that incorporates the inherent variable efficiency of generating perfectly strand-specific libraries. Applying the method to new ssRNA-seq data from whole-root and cell-type-specific Arabidopsis libraries confirmed most of the known cis-NAT pairs and identified 918 additional cis-NAT pairs. Newly identified cis-NAT pairs are supported by polyadenylation data, alternative splicing patterns, and RT-PCR validation. We found 209 cis-NAT pairs that have opposite expression levels in neighboring cell types, implying cell-type-specific roles for cis-NATs. By integrating a genome-wide epigenetic profile of Arabidopsis, we identified a unique chromatin signature of cis-NATs, suggesting a connection between cis-NAT transcription and chromatin modification in plants. An analysis of small-RNA sequencing data showed that~4% of cis-NAT pairs produce putative cis-NAT-induced siRNAs. Taken together, our data and analyses illustrate the potential for multifaceted regulatory roles of plant cis-NATs.

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“…Recently, bioinformatics analysis of the human transcriptome correlated antisense (AS) transcription with alternative splicing of overlapping sense-strand transcripts (Morrissy et al 2011). The aberrantly spliced and terminated transcripts at Cdk5rap1 (Druker et al 2004) were attributed tentatively to possible AS transcription initiated from the intronic ERV promoter.…”

Section: Transcriptional Variation Due To Polymorphic Ervsmentioning

confidence: 99%

Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance

Li¹,

Akagi²,

Hu³

et al. 2012

Genome Res.

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Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, facilitating a comparison of gene expression in the presence or absence of local insertions. Polymorphic ERVs occur relatively infrequently in gene introns and are particularly depleted from genes involved in embryogenesis or that are highly expressed in embryonic stem cells. Their genomic distribution implies ongoing negative selection due to deleterious effects on gene expression and function. A polymorphic, intronic ERV at Slc15a2 triggers up to 49-fold increases in premature transcriptional termination and up to 39-fold reductions in full-length transcripts in adult mouse tissues, thereby disrupting protein expression and functional activity. Prematurely truncated transcripts also occur at Polr1a, Spon1, and up to~5% of other genes when intronic ERV polymorphisms are present. Analysis of expression quantitative trait loci (eQTLs) in recombinant BxD mouse strains demonstrated very strong genetic associations between the polymorphic ERV in cis and disrupted transcript levels. Premature polyadenylation is triggered at genomic distances up to >12.5 kb upstream of the ERV, both in cis and between alleles. The parent of origin of the ERV is associated with variable expression of nonterminated transcripts and differential DNA methylation at its 59-long terminal repeat. This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity.

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Extensive relationship between antisense transcription and alternative splicing in the human genome

Cited by 72 publications

References 59 publications

Long Noncoding RNAs: Past, Present, and Future

Long Noncoding RNAs: Past, Present, and Future

Integrated detection of natural antisense transcripts using strand-specific RNA sequencing data

Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance

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