Tandem chimerism as a means to increase protein complexity in the human genome

Parra, Genı́s; Reymond, Alexandre; Dabbouseh, Noura M.; Dermitzakis, Emmanouil T.; Castelo, Robert; Thomson, Timothy M.; Antonarakis, Stylianos E.; Guigó, Roderic

doi:10.1101/gr.4145906

Cited by 184 publications

(213 citation statements)

References 39 publications

(42 reference statements)

Supporting

Mentioning

195

Contrasting

Order By: Relevance

“…Our deep-sequencing results therefore suggest that chimeric RNAs may be more prevalent in human cells than previously thought. The results thus significantly extend the observation made by a recent in silico analysis of ESTs and cDNAs in the National Center for Biotechnology Information databases, which independently estimated that as much as 5% of the human genome could transcribe chimeric sequences (19).…”

Section: Discussionsupporting

confidence: 71%

Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing

Kannan¹,

Wang

Wang³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

162

166

View full text Add to dashboard Cite

Transcription-induced chimeric RNAs, possessing sequences from different genes, are expected to increase the proteomic diversity through chimeric proteins or altered regulation. Despite their importance, few studies have focused on chimeric RNAs especially regarding their presence/roles in human cancers. By deep sequencing the transcriptome of 20 human prostate cancer and 10 matched benign prostate tissues, we obtained 1.3 billion sequence reads, which led to the identification of 2,369 chimeric RNA candidates. Chimeric RNAs occurred in significantly higher frequency in cancer than in matched benign samples. Experimental investigation of a selected 46 set led to the confirmation of 32 chimeric RNAs, of which 27 were highly recurrent and previously undescribed in prostate cancer. Importantly, a subset of these chimeras was present in prostate cancer cell lines, but not detectable in primary human prostate epithelium cells, implying their associations with cancer. These chimeras contain discernable 5′ and 3′ splice sites at the RNA junction, indicating that their formation is mediated by splicing. Their presence is also largely independent of the expression of parental genes, suggesting that other factors are involved in their production and regulation. One chimera, TMEM79-SMG5 , is highly differentially expressed in human cancer samples and therefore a potential biomarker. The prevalence of chimeric RNAs may allow the limited number of human genes to encode a substantially larger number of RNAs and proteins, forming an additional layer of cellular complexity. Together, our results suggest that chimeric RNAs are widespread, and increased chimeric RNA events could represent a unique class of molecular alteration in cancer.

show abstract

Section: Discussionsupporting

confidence: 71%

Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing

Kannan¹,

Wang

Wang³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

162

166

View full text Add to dashboard Cite

show abstract

“…However, recent in-depth annotations projects have had the effect of blurring gene boundaries, up to challenging the definition of a gene [57,58]. Also, since cases of overlapping transcripts from hitherto distinctly annotated genes are increasingly reported [59,60], genes can no longer be regarded as isolated units of transcription. Transcription Induced Chimeras [60][61][62], i.e., genes that are fused by a transcript sharing at least one splice site with either one of them, are to be respected when investigating the phenomenon of AS.…”

Section: Discussionmentioning

confidence: 99%

A General Definition and Nomenclature for Alternative Splicing Events

Sammeth¹,

Foissac²,

Guigó³

2008

SciVee

Self Cite

View full text Add to dashboard Cite

Understanding the molecular mechanisms responsible for the regulation of the transcriptome present in eukaryotic cells is one of the most challenging tasks in the postgenomic era. In this regard, alternative splicing (AS) is a key phenomenon contributing to the production of different mature transcripts from the same primary RNA sequence. As a plethora of different transcript forms is available in databases, a first step to uncover the biology that drives AS is to identify the different types of reflected splicing variation. In this work, we present a general definition of the AS event along with a notation system that involves the relative positions of the splice sites. This nomenclature univocally and dynamically assigns a specific ''AS code'' to every possible pattern of splicing variation. On the basis of this definition and the corresponding codes, we have developed a computational tool (AStalavista) that automatically characterizes the complete landscape of AS events in a given transcript annotation of a genome, thus providing a platform to investigate the transcriptome diversity across genes, chromosomes, and species. Our analysis reveals that a substantial part-in human more than a quarter-of the observed splicing variations are ignored in common classification pipelines. We have used AStalavista to investigate and to compare the AS landscape of different reference annotation sets in human and in other metazoan species and found that proportions of AS events change substantially depending on the annotation protocol, species-specific attributes, and coding constraints acting on the transcripts. The AStalavista system therefore provides a general framework to conduct specific studies investigating the occurrence, impact, and regulation of AS.

show abstract

“…Transcription-induced RNA chimeras have been previously recognized and thought to occur in physiologically normal tissues, or less frequently in neoplastic tissues wherein they are hypothesized to confer tumorigenic signals via gain of function or loss of function effects (39)(40)(41). Additionally, intergenic splicing events resulting in differential expression of chimeric transcripts in tumoral tissues compared with normal tissues have been observed, although the selection mechanisms for maintaining these splicing events and chimeras are poorly understood (39,40,42,43).…”

Section: (Pp1)mentioning

confidence: 99%

“…Additionally, intergenic splicing events resulting in differential expression of chimeric transcripts in tumoral tissues compared with normal tissues have been observed, although the selection mechanisms for maintaining these splicing events and chimeras are poorly understood (39,40,42,43). Interestingly, it has been recognized that these intergenic splicing events between heterologous genes may mark the breakpoint sites that are targeted by chromosomal translocations at the genomic level (42,44).…”

Section: (Pp1)mentioning

confidence: 99%

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Velusamy

Palanisamy

Kalyana-Sundaram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia. chimera splicing | next-generation sequencing | serine/threonine phosphatase PP1-beta catalytic subunit | B-lymphoid malignancy B -cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in adults in Western countries (1). The most common recurrent cytogenetic abnormality in CLL is a deletion involving the 13q14.3 locus, which occurs in 50% of cases and targets miR-16-1, miR-15a, and DLEU2 (2-4). Twenty percent of CLLs exhibit trisomy 12 (5). Other recurrent abnormalities in CLL include del 11q22-23 (ATM) and 17p13 (targeting p53) (6, 7). Of clinical relevance, IgV mutational status and zeta-chain associated protein kinase-70 kD (ZAP-70) expression have been associated with distinct prognostic categories of B-CLL (8-10). Recently, mutations in NOTCH1 (12.2%), MYD88 (2.9%), and XPO1 (2.4%) have been identified using next-generation sequencing (11, 12). The NOTCH1 mutations occur more frequently in cases with unmutated variable regions of the Ig heavy chain genes, whereas the MYD88 mutations occur more frequently in mutated cases (11).Although the role of genomic events is well established in the pathogenesis of cancers, the contribution of posttranscriptional RNA processing, which plays a fundamental role in control of protein expression, is less well understood.Alternative splicing can affect the translation, localization, or degradation of mRNA (13) and frequently results in the production of multiple and functionally distinct protein isoforms (14). Importantly, alternative splicing and expression of abnormal splicing chimeras may contribute to cancer pathogenesis and are associated with prognostic significance (15, 16). For exam...

show abstract

Tandem chimerism as a means to increase protein complexity in the human genome

Cited by 184 publications

References 39 publications

Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing

Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing

A General Definition and Nomenclature for Alternative Splicing Events

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Contact Info

Product

Resources

About