Chimeric RNAs in cancer and normal physiology

Chwalenia, Katarzyna; Facemire, Loryn; Li, Hui

doi:10.1002/wrna.1427

Cited by 52 publications

(65 citation statements)

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“…Fusion transcripts and their encoded products were earlier perceived to be an aberration with negative outcome -owing to their abundance in cancers [16][17][18] . A few isolated studies have reported the existence of fusion RNAs within the normal human genome 19,20 .…”

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confidence: 99%

Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues

Mehani

Narta

Paul

et al. 2020

Sci Rep

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Fusion transcripts can contribute to diversity of molecular networks in the human cortex. In this study, we explored the occurrence of fusion transcripts in normal human cortex along with single neurons and astrocytes. We identified 1305 non-redundant fusion events from 388 transcriptomes representing 59 human cortices and 329 single cells. Our results indicate while the majority of fusion transcripts in human cortex are intra-chromosomal (85%), events found in single neurons and astrocytes were primarily inter-chromosomal (80%). The number of fusions in single neurons was significantly higher than that in single astrocytes (p < 0.05), indicating fusion as a possible contributor towards transcriptome diversity in neuronal cells. The identified fusions were largely private and 4 specific recurring events were found both in cortex and in single neurons but not in astrocytes. We found a significant increase in the number of fusion transcripts in human brain with increasing age both in single cells and whole cortex (p < 0.0005 and < 0.005, respectively). This is likely one of the many possible contributors for the inherent plasticity of the adult brain. The fusion transcripts in fetal brain were enriched for genes for long-term depression; while those in adult brain involved genes enriched for long-term potentiation pathways. Our findings demonstrate fusion transcripts are naturally occurring phenomenon spanning across the health-disease continuum, and likely contribute to the diverse molecular network of human brain. Biological systems utilize their built-in flexibility to respond to unknown situations that challenge their 'fitness' to adapt and respond. This flexibility usually increases with increased complexity and diversity of more recently evolved species. Human biology, in particular of the human brain, is one of the most diverse natural systems. At a molecular level, this flexibility is created and maintained by contributions from all layers of information-namely, DNA, RNA and Proteins, usually following an increasing order of diversity. We have earlier reported the extent of DNA level diversity and its possible role due to somatic single nucleotide variations in normal human brain 1. Earlier studies have reported wide variety of DNA level diversity in neuron rich regions of normal human brainranging from whole chromosomes 2,3 , large-scale retro transpositions 4,5 , and copy number variations at the single neuron level 6. We have also shown the diversity in the non-coding RNA of human brain attributed through the RNA editing mechanisms in miRNAs and their possible role in biological outcome 7. In this study, we embarked on investigation of fusion transcripts in human brain-another possible mechanism by which the transcriptome can contribute to the diversity of complex systems.

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confidence: 99%

Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues

Mehani

Narta

Paul

et al. 2020

Sci Rep

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“…Chimeras A-J had different combinations of exons, most probably derived from alternative splicing of this three-gene primary RNA transcript. The most frequent cis-SAGe splicing pattern (termed the 2'-2' rule) occurs between the second-to-last exon of the 59 gene and the second exon of the 39 gene (Parra et al, 2006;Jia et al, 2016;Chwalenia et al, 2017). Among the 12 chimeras we identified, two were formed according to this 2'-2' rule: Chimera F had UGT2B15 exon 5 spliced to UGT2B29P2 exon 2 and chimera H had UGT2B15 exon 5 spliced to UGT2B17 exon 2.…”

Section: Discussionmentioning

confidence: 99%

“…Chimeric transcripts can be generated by trans-splicing or cis-splicing (Chwalenia et al, 2017). Trans-splicing is a noncanonical splicing process by which exons of two different primary transcripts are spliced into a single mRNA (Lei et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…All alternatively spliced UGT transcripts reported so far contain exons that are located within the boundaries of single UGT gene locus. Transcripts that contain exons from more than one gene locus are termed chimeric transcripts (Parra et al, 2006) and have been found in both normal and cancer tissues (Chwalenia et al, 2017). Several mechanisms contribute to the formation of chimeric transcripts, including trans-splicing, cis-splicing of adjacent genes (termed cis-SAGe), and chromosomal translocation (Lei et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Intergenic Splicing between Four AdjacentUGTGenes (2B15, 2B29P2, 2B17, 2B29P1) Gives Rise to Variant UGT Proteins That Inhibit Glucuronidation via Protein-Protein Interactions

Hulin

Wijayakumara

et al. 2018

Mol Pharmacol

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Recent studies have investigated alternative splicing profiles of UDP-glucuronosyltransferase genes and identified over 130 different alternatively spliced UGT transcripts. Although genes are highly clustered, the formation of chimeric transcripts by intergenic splicing between two or more genes has not yet been reported. This study identified 12 chimeric transcripts (chimeras A-L) containing exons from two or three genes of the four neighboring genes (, ,, and ) in human liver and prostate cancer cells. These chimeras typically contain the first five exons of or (exons 1-5) spliced to a terminal exon (exon 6) from a downstream gene. Hence they encode truncated UGTs with novel C-terminal peptides. Functional assays of representative chimeric UGT proteins (termed chimeric UGT2B15 and chimeric UGT2B17) showed that they are inactive and can repress the activity of wild-type UGTs. Coimmunoprecipitation assays demonstrated heterotypic interactions between chimeric UGT2B15 (or chimeric UGT2B17) and the UGT2B7 protein. Thus oligomerization of the chimeric UGTs with wild-type UGTs may explain their inhibitory activity. Studies in breast and prostate cancer cells showed that both wild-type and chimeric UGT2B15 and UGT2B17 transcripts are regulated in a similar way at the transcriptional level by sex hormones through their canonical promoters but are differentially regulated at the post-transcriptional level by micro-RNA 376c via their unique 3'-untranslated regions. In conclusion, the formation of chimeric transcripts by intergenic splicing among genes represents a novel mechanism contributing to the diversity of the human UGT transcriptome and proteome. The differential post-transcriptional regulation of wild-type and variant transcripts by micro-RNAs may contribute to their deregulated expression in cancer.

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“…Dominant among the so far detected cis-SAGe is the fusion point at the second exon of the 3´ gene [7].…”

Section: Introductionmentioning

confidence: 99%

Fusion transcript detection using spatial transcriptomics

Friedrich

Sonnhammer

2020

Preprint

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Background Fusion transcripts are involved in tumourigenesis and play a crucial role in tumour heterogeneity, tumour evolution and cancer treatment resistance. However, fusion transcripts have not been studied at high spatial resolution in tissue sections due to the lack of full-length transcripts with spatial information. New high-throughput technologies like spatial transcriptomics measure the transcriptome of tissue sections on almost single-cell level. While this technique does not allow for direct detection of fusion transcripts, we show that they can be inferred using the relative poly(A) tail abundance of the involved parental genes. Method We present a new method STfusion, which uses spatial transcriptomics to infer the presence and absence of poly(A) tails. A fusion transcript lacks a poly(A) tail for the 5´ gene and has an elevated number of poly(A) tails for the 3´ gene. Its expression level is defined by the upstream promoter of the 5´ gene. STfusion measures the difference between the observed and expected number of poly(A) tails with a novel C-score. Results We verified the STfusion ability to predict fusion transcripts on HeLa cells with known fusions. STfusion and C-score applied to clinical prostate cancer data revealed the spatial distribution of the cis-SAGe SLC45A3-ELK4 in 12 tissue sections with almost single-cell resolution. The cis-SAGe occurred in disease areas, e.g. inflamed, prostatic intraepithelial neoplastic, or cancerous areas, and occasionally in normal glands. Conclusions STfusion detects fusion transcripts in cancer cell line and clinical tissue data, and distinguishes chimeric transcripts from chimeras caused by trans-splicing events. With STfusion and the use of C-scores, fusion transcripts can be spatially localised in clinical tissue sections on almost single cell level.

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Chimeric RNAs in cancer and normal physiology

Cited by 52 publications

References 167 publications

Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues

Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues

Intergenic Splicing between Four AdjacentUGTGenes (2B15, 2B29P2, 2B17, 2B29P1) Gives Rise to Variant UGT Proteins That Inhibit Glucuronidation via Protein-Protein Interactions

Fusion transcript detection using spatial transcriptomics

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