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

British Columbia Cancer Agency, Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada.
Genome Research (Impact Factor: 14.63). 06/2011; 21(8):1203-12. DOI: 10.1101/gr.113431.110
Source: PubMed


To analyze the relationship between antisense transcription and alternative splicing, we developed a computational approach for the detection of antisense-correlated exon splicing events using Affymetrix exon array data. Our analysis of expression data from 176 lymphoblastoid cell lines revealed that the majority of expressed sense-antisense genes exhibited alternative splicing events that were correlated to the expression of the antisense gene. Most of these events occurred in areas of sense-antisense (SAS) gene overlap, which were significantly enriched in both exons and nucleosome occupancy levels relative to nonoverlapping regions of the same genes. Nucleosome occupancy was highly correlated with Pol II abundance across overlapping regions and with concomitant increases in local alternative exon usage. These results are consistent with an antisense transcription-mediated mechanism of splicing regulation in normal human cells. A comparison of the prevalence of antisense-correlated splicing events between individuals of Mormon versus African descent revealed population-specific events that may indicate the continued evolution of new SAS loci. Furthermore, the presence of antisense transcription was correlated to alternative splicing across multiple metazoan species, suggesting that it may be a conserved mechanism contributing to splicing regulation.

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Available from: Malachi Griffith, Oct 07, 2015
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    • "Expression of antisense transcripts and alternative splicing are often correlated in plants and human cells, and this correlation may extend to multiple metazoan species (Jen et al., 2005; Morrissy et al., 2011). Regions of sense/antisense overlap are associated with higher nucleosome density and RNA polymerase II accumulation (Morrissy et al., 2011). Bidirectional transcription can be a source of endogenous small interfering RNAs (endosiRNAs ) (Lehner et al., 2002; Okamura et al., 2008), which, in turn, can induce chromatin modifications and influence transcription elongation via the activity of Argonaute pathways (Burkhart et al., 2011; Guang et al., 2010). "
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    ABSTRACT: Many eukaryotic genes contain embedded antisense transcripts and repetitive sequences of unknown function. We report that male germline-specific expression of an antisense transcript contained in an intron of C. elegans Target of Rapamycin (TOR, let-363) is associated with (1) accumulation of endo-small interfering RNAs (siRNAs) against an embedded Helitron transposon and (2) activation of an alternative 3' splice site of TOR. The germline-specific Argonaute proteins PRG-1 and CSR-1, which participate in self/nonself RNA recognition, antagonistically regulate the generation of these endo-siRNAs, TOR mRNA levels, and 3' splice-site selection. Supply of exogenous double-stranded RNA against the region of sense/antisense overlap reverses changes in TOR expression and splicing and suppresses the progressive multigenerational sterility phenotype of prg-1 mutants. We propose that recognition of a "nonself" intronic transposon by endo-siRNAs/the piRNA system provides physiological regulation of expression and alternative splicing of a host gene that, in turn, contributes to the maintenance of germline function across generations.
    Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.016 · 8.36 Impact Factor
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    • "Regarding gene splicing modulation, it has been long known to involve the small nuclear RNAs (snRNAs) (32), which along with the SR proteins and hnRNPs are components of the spliceosome. While a computational analysis has revealed an extensive relationship between long antisense RNAs and alternative splicing in the human genome (33), only a very limited number of lncRNAs has been shown to directly modulate alternative mRNA splicing. Thus, an endogenous transcript antisense to N-myc was shown to form an RNA-RNA duplex with the sense mRNA and to cause retention of N-myc intron 1 (34), however, the functional significance of this alternative splicing was not assessed (34). "
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    Nucleic Acids Research 07/2014; 42(13). DOI:10.1093/nar/gku561 · 9.11 Impact Factor
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    • "The recent use of next-generation sequencing technologies has shed new light on these transcription events and introduced a plethora of non-coding transcripts, including antisense transcripts [12]–[14]. Genome-wide studies have shown that many genes have antisense counterparts, stimulating investigations into their functional significance [15]. Indeed, up to 72% of transcripts have been demonstrated to have antisense partners in the human and mouse transcriptomes [16]. "
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    ABSTRACT: The horse is an optimal model organism for studying the genomic response to exercise-induced stress, due to its natural aptitude for athletic performance and the relative homogeneity of its genetic and environmental backgrounds. Here, we applied RNA-sequencing analysis through the use of SOLiD technology in an experimental framework centered on exercise-induced stress during endurance races in equine athletes. We monitored the transcriptional landscape by comparing gene expression levels between animals at rest and after competition. Overall, we observed a shift from coding to non-coding regions, suggesting that the stress response involves the differential expression of not annotated regions. Notably, we observed significant post-race increases of reads that correspond to repeats, especially the intergenic and intronic L1 and L2 transposable elements. We also observed increased expression of the antisense strands compared to the sense strands in intronic and regulatory regions (1 kb up- and downstream) of the genes, suggesting that antisense transcription could be one of the main mechanisms for transposon regulation in the horse under stress conditions. We identified a large number of transcripts corresponding to intergenic and intronic regions putatively associated with new transcriptional elements. Gene expression and pathway analysis allowed us to identify several biological processes and molecular functions that may be involved with exercise-induced stress. Ontology clustering reflected mechanisms that are already known to be stress activated (e.g., chemokine-type cytokines, Toll-like receptors, and kinases), as well as "nucleic acid binding" and "signal transduction activity" functions. There was also a general and transient decrease in the global rates of protein synthesis, which would be expected after strenuous global stress. In sum, our network analysis points toward the involvement of specific gene clusters in equine exercise-induced stress, including those involved in inflammation, cell signaling, and immune interactions.
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