Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein-coding RNAs

Abstract

BackgroundThe genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein-coding RNAs. Despite increasing numbers of functional reports of individual long non-coding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein-coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental in the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identified lncRNAs expressed differentially in response to oncologically relevant processes and cell-cycle, p53 and STAT3 pathways, using tiling arrays.ResultsWe found that up to 80% of the pathway-triggered transcriptional responses are non-coding. Among these we identified very large macroRNAs with pathway-specific expression patterns and demonstrated that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein-coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed.ConclusionsIt has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events.

The Landscape of long noncoding RNA classification

“…Building transcribed regions based on RNA-seq profiling of total RNA (rather than the polyA+ fraction, see below) led to the discovery that intergenic space encodes thousands of very long intergenic non-coding RNAs (vlincRNAs), whose primary transcripts can range in length from 50 kb to 1MB [28, 29, 41]. Spanning at least 10% of human genome [5, 29], vlincRNAs have been implicated in important biological processes such as pluripotency [29], cancer [28, 29], apoptosis [29], cell-cycle progression [28, 42], and cellular senescence [41].…”

Comparison of splice sites reveals that long noncoding RNAs are evolutionarily well conserved

“…A substantial portion of the transcriptome appears as mRNA-like nonprotein-coding transcripts (Maeda et al 2006; The ENCODE Project Consortium 2007), although there is ample evidence for the existence of many other classes of transcripts, ranging from small structured ncRNAs (Washietl et al 2005) to intronic transcripts (Louro et al 2009), independently transcribed UTRs (Mercer et al 2011), and giant "macroRNAs" (Kapranov et al 2010;Hackermüller et al 2014). Despite their abundance, the evolutionary history of these transcripts is still poorly understood.…”

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

“…Interestingly, a part of those transcripts was expressed in response to cell cycle, p53 and STAT3 pathway activation 44. A novel four‐lncRNA signature that accurately predicts survival in GBM patients was recently reported, and results of a functional analysis suggest that co‐expressed genes tend to cluster within nine immune‐related processes and four biological pathways 45…”