Academic journal article Genetics

Emerging Properties and Functional Consequences of Noncoding Transcription

Academic journal article Genetics

Emerging Properties and Functional Consequences of Noncoding Transcription

Article excerpt

RNA Polymerase II (RNAPII) pervasively transcribes genomes, generating all protein-coding messenger RNAs (mRNAs) and many noncoding RNAs longer than 200 nucleotides (long noncoding RNAs; lncRNAs) (Jensen etai. 2013). Today, it is accepted that most eukaryotic genomes generate an abundance of lncRNA transcripts but, for technical reasons discussed below, many lncRNAs escaped detection until recently. Consequently, only a relatively small fraction of lncRNAs have been functionally characterized, unlike other classes of well-characterized short noncoding RNAs generated by RNAPII (e.g., micro RNAs, small interfering RNAs, small nuclear RNAs, and small nucleolar RNAs). The fact that lncRNAs are defined by their size rather than any common function is itself evidence that this grouping is arbitrary and, indeed, relatively little is yet known about the roles of this heterogeneous class of noncoding transcripts.

Superficially, mRNAs and lncRNAs share many common features. Both classes of transcripts are 5'-capped, may be multiexonic, alternatively spliced, and 3' polyadenylated. However, unlike stable mature mRNAs that are exported to the cytoplasm for protein synthesis, lncRNAs are predominantly nuclear and often rapidly degraded. In fact, subclasses of lncRNAs are distinguished by different decay pathways responsible for their degradation (Marquardt et ai. 2011), which are often targeted during or shortly after synthesis (Houseley and Tollervey 2009). As a class, lncRNAs exhibit poor sequence conservation between species. However, lack of sequence similarity does not necessarily rule out function as several functionally conserved lncRNAs exhibit little or no detectable primary sequence homology between closely related species, as is the case for the X-inactivation-specific transcript XIST, which is responsible for initiating dosage compensation in female mammals (Pang et ai. 2006). Moreover, some lncRNA promoters, splice sites, and positions with respect to flanking genes are preserved through evolution (Ulitsky 2016), indicating that lncRNA transcription at equivalent positions can be conserved, even though this results in RNA products that lack obvious homology.

Putative functions have been assigned to an ever-increasing number of relatively high- and low-abundance lncRNAs in diverse organisms [as reviewed extensively in Mercer et ai. (2009), Ponting et ai. (2009), Rinn and Chang (2012), Geisler and Coller (2013), Kung et ai. (2013), Engreitz et ai. (2016), Quinn and Chang (2016)]. However, the mechanisms by which specific lncRNAs achieve their effects on gene regulation are complicated by the fact that lncRNA transcription can itself impinge on the activity of nearby genes (Kornienko et al. 2013). This is problematic since it is experimentally difficult to distinguish the roles of any given lncRNA from the unexpected consequences resulting from the act of its transcription. For example, the imprinted mouse lncRNA Aim was initially proposed to induce targeted repression of the Igf2r gene by mediating chromatin looping, but later analyses revealed that the Aim lncRNA is itself dispensable as the act of transcribing this locus is sufficient to induce Igf2r silencing (Latos et al 2012). Similarly, new lncRNA studies regularly challenge or even overturn the interpretations of earlier ones (Cech and Steitz 2014). This is partly because generally accepted methods for clearly assigning function to lncRNAs have only recently been set out and adopted (Bassett et al. 2014; Goff and Rinn 2015). Ultimately, the idea that the act of noncoding transcription can itself have important functional outcomes provides an intriguing paradigm for how widespread transcription, even when such acts fail to produce stable lncRNAs ("cryptic transcription"), can serve important biological roles in both dense yeast genomes as well as in much larger genomes of multicellular eukaryotes.

Here, we discuss recently emerging features that distinguish coding from noncoding transcription in yeast and human, and outline how these differences might have important implications for the functional consequences of pervasive noncoding transcription both proximal to and far from protein-coding genes. …

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