Chimeras taking shape: Potential functions of proteins encoded by chimeric RNA transcripts

Abstract

Chimeric RNAs comprise exons from two or more different genes and have the potential to encode novel proteins that alter cellular phenotypes. To date, numerous putative chimeric transcripts have been identified among the ESTs isolated from several organisms and using high throughput RNA sequencing. The few corresponding protein products that have been characterized mostly result from chromosomal translocations and are associated with cancer. Here, we systematically establish that some of the putative chimeric transcripts are genuinely expressed in human cells. Using high throughput RNA sequencing, mass spectrometry experimental data, and functional annotation, we studied 7424 putative human chimeric RNAs. We confirmed the expression of 175 chimeric RNAs in 16 human tissues, with an abundance varying from 0.06 to 17 RPKM (Reads Per Kilobase per Million mapped reads). We show that these chimeric RNAs are significantly more tissue-specific than non-chimeric transcripts. Moreover, we present evidence that chimeras tend to incorporate highly expressed genes. Despite the low expression level of most chimeric RNAs, we show that 12 novel chimeras are translated into proteins detectable in multiple shotgun mass spectrometry experiments. Furthermore, we confirm the expression of three novel chimeric proteins using targeted mass spectrometry. Finally, based on our functional annotation of exon organization and preserved domains, we discuss the potential features of chimeric proteins with illustrative examples and suggest that chimeras significantly exploit signal peptides and transmembrane domains, which can alter the cellular localization of cognate proteins. Taken together, these findings establish that some chimeric RNAs are translated into potentially functional proteins in humans.

How life changes itself: The Read–Write (RW) genome

“…Trans-splicing is a regular feature of the genome expression process in certain organisms [47], and it serves as a mechanism for protein diversification by creating novel exon combinations in many taxa [48]. Recent data indicate that trans-splicing occurs more frequently than previously believed [49].…”

Transformative Impact of Proteomics on Cardiovascular Health and Disease

“…Proteome complexity is highlighted by recent studies showing that phenotype is not entirely determined by information encoded in the translated genome; PTMs, noncoding RNAs (including microRNAs), epigenetic changes, and protein-protein interaction networks affect phenotype. 5,6 The ultimate goal of cardiovascular proteomics is to harness and better comprehend this molecular complexity as a means to discover new, effective strategies for the prevention, identification, and treatment of cardiovascular disease.…”

Functional transcriptomics in the post-ENCODE era

“…Furthermore, it has been shown that transcription proceeds in the 59 direction beyond 65% of ENCODE gene boundaries, often integrating into the exonic structure of upstream genes; the role of such ''chimeric read-through RNAs'' remains largely unclear (Fig. 1B, model vii;Gingeras 2009;Djebali et al 2012b;Frenkel-Morgenstern et al 2012). Unfortunately, contemporary RNA-seq data sets remain a source of technical frustration; the reads generated are short in length, and it is no trivial task to assemble these fragments into full-length transcript models (Wang et al 2009;Martin and Wang 2011;Ozsolak and Milos 2011).…”

“…In particular, a locus may generate multiple transcripts due to alternative splicing (AS) ) and read-through transcription (Fig. 1B;Frenkel-Morgenstern et al 2012), while the discovery of long noncoding RNAs (lncRNAs) suggests that most human transcripts may not encode proteins (Rinn and Chang 2012). In fact, the bulk of the genome appears to be ''pervasively'' transcribed (The ENCODE Project Consortium 2012), although the functional relevance of this process remains a source of debate (Ball 2013;Doolittle 2013;Graur et al 2013).…”