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Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells.

ABSTRACT: Transcriptionally non-co-linear (NCL) transcripts can originate from trans-splicing (trans-spliced RNA; 'tsRNA') or cis-backsplicing (circular RNA; 'circRNA'). While numerous circRNAs have been detected in various species, tsRNAs remain largely uninvestigated. Here, we utilize integrative transcriptome sequencing of poly(A)- and non-poly(A)-selected RNA-seq data from diverse human cell lines to distinguish between tsRNAs and circRNAs. We identified 24,498 NCL events and found that a considerable proportion (20-35%) of them arise from both tsRNAs and circRNAs, representing extensive alternative trans-splicing and cis-backsplicing in human cells. We show that sequence generalities of exon circularization are also observed in tsRNAs. Recapitulation of NCL RNAs further shows that inverted Alu repeats can simultaneously promote the formation of tsRNAs and circRNAs. However, tsRNAs and circRNAs exhibit quite different, or even opposite, expression patterns, in terms of correlation with the expression of their co-linear counterparts, expression breadth/abundance, transcript stability, and subcellular localization preference. These results indicate that tsRNAs and circRNAs may play different regulatory roles and analysis of NCL events should take the joint effects of different NCL-splicing types and joint effects of multiple NCL events into consideration. This study describes the first transcriptome-wide analysis of trans-splicing and cis-backsplicing, expanding our understanding of the complexity of the human transcriptome.

SUBMITTER: Chuang TJ

PROVIDER: S-EPMC6283421 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells.

Chuang Trees-Juen TJ Chen Yen-Ju YJ Chen Chia-Ying CY Mai Te-Lun TL Wang Yi-Da YD Yeh Chung-Shu CS Yang Min-Yu MY Hsiao Yu-Ting YT Chang Tien-Hsien TH Kuo Tzu-Chien TC Cho Hsin-Hua HH Shen Chia-Ning CN Kuo Hung-Chih HC Lu Mei-Yeh MY Chen Yi-Hua YH Hsieh Shan-Chi SC Chiang Tai-Wei TW

Nucleic acids research 20180401 7

Transcriptionally non-co-linear (NCL) transcripts can originate from trans-splicing (trans-spliced RNA; 'tsRNA') or cis-backsplicing (circular RNA; 'circRNA'). While numerous circRNAs have been detected in various species, tsRNAs remain largely uninvestigated. Here, we utilize integrative transcriptome sequencing of poly(A)- and non-poly(A)-selected RNA-seq data from diverse human cell lines to distinguish between tsRNAs and circRNAs. We identified 24,498 NCL events and found that a considerable ...[more]

PMID: 29385530

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Project description:The killer-cell Ig-like receptors (KIR) form a multigene entity involved in modulating immune responses through interactions with MHC class I molecules. The complexity of the KIR cluster is reflected by, for instance, abundant levels of allelic polymorphism, gene copy number variation, and stochastic expression profiles. The current transcriptome study involving human and macaque families demonstrates that KIR family members are also subjected to differential levels of alternative splicing, and this seems to be gene dependent. Alternative splicing may result in the partial or complete skipping of exons, or the partial inclusion of introns, as documented at the transcription level. This post-transcriptional process can generate multiple isoforms from a single KIR gene, which diversifies the characteristics of the encoded proteins. For example, alternative splicing could modify ligand interactions, cellular localization, signaling properties, and the number of extracellular domains of the receptor. In humans, we observed abundant splicing for KIR2DL4, and to a lesser extent in the lineage III KIR genes. All experimentally documented splice events are substantiated by in silico splicing strength predictions. To a similar extent, alternative splicing is observed in rhesus macaques, a species that shares a close evolutionary relationship with humans. Splicing profiles of Mamu-KIR1D and Mamu-KIR2DL04 displayed a great diversity, whereas Mamu-KIR3DL20 (lineage V) is consistently spliced to generate a homolog of human KIR2DL5 (lineage I). The latter case represents an example of convergent evolution. Although just a single KIR splice event is shared between humans and macaques, the splicing mechanisms are similar, and the predicted consequences are comparable. In conclusion, alternative splicing adds an additional layer of complexity to the KIR gene system in primates, and results in a wide structural and functional variety of KIR receptors and its isoforms, which may play a role in health and disease.

Project description:BACKGROUND: Schistosoma japonicum is a pathogen of the phylum Platyhelminthes that causes zoonotic schistosomiasis in China and Southeast Asian countries where a lack of efficient measures has hampered disease control. The development of tools for diagnosis of acute and chronic infection and for novel antiparasite reagents relies on understanding the biological mechanisms that the parasite exploits. RESULTS: In this study, the polyadenylated transcripts from the male and female S. japonicum were sequenced using a high-throughput RNA-seq technique. Bioinformatic and experimental analyses focused on post-transcriptional RNA processing, which revealed extensive alternative splicing events in the adult stage of the parasite. The numbers of protein-coding sequences identified in the transcriptomes of the female and male S. japonicum were 15,939 and 19,501 respectively, which is more than predicted from the annotated genome sequence. Further, we identified four types of post-transcriptional processing, or alternative splicing, in both female and male worms of S. japonicum: exon skipping, intron retention, and alternative donor and acceptor sites. Unlike mammalian organisms, in S. japonicum, the alternative donor and acceptor sites were more common than the other two types of post-transcriptional processing. In total, respectively 13,438 and 16,507 alternative splicing events were predicted in the transcriptomes of female and male S. japonicum. CONCLUSIONS: By using RNA-seq technology, we obtained the global transcriptomes of male and female S. japonicum. These results further provide a comprehensive view of the global transcriptome of S. japonicum. The findings of a substantial level of alternative splicing events dynamically occurring in S. japonicum parasitization of mammalian hosts suggest complicated transcriptional and post-transcriptional regulation mechanisms employed by the parasite. These data should not only significantly improve the re-annotation of the genome sequences but also should provide new information about the biology of the parasite.

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Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells.

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Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells.

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