One of the more striking biological discoveries of the past decade has been the extent of transcription from regions of the genome that do not code for proteins. The resulting non-coding (nc)RNA has been the subject of lively debate. Much of this debate has focused on what proportion of this ncRNA is likely to be functional. Two opposing PloS Biology papers from 2011 offer a good starting point, arguing either that ncRNAs probably represent functional transcripts, or that while substantial ncRNA transcription exists, it is often not biologically meaningful, representing either technical artefact or undirected transcriptional ‘noise’. The debate reared its head again last year with the publication of ENCODE, whose inclusion of any biochemical activity in its definition of ‘functional’ was subject to complaint.
The difficulty of arriving at a meaningful definition of function for ncRNAs is highlighted by a review published in BMC Biology from Florian Pauler, Denise Barlow and colleagues at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. While we usually think of transcription as simply a necessary step in the production of RNA, which goes on to either be translated into protein or to perform its own catalytic function, the authors summarise instances where the process of RNA transcription itself regulates nearby genes. This kind of transcription-mediated silencing, termed “transcriptional interference”, has been noted before, but usually involves two protein-coding genes that are themselves functional. Pauler and colleagues highlight cases where the transcribed ncRNA may well be disposable, and the transcription process is the key functional element.
The number of ways transcription can mediate gene regulation is surprisingly high. Gene promoters are the targets of transcriptional interference in many of the cases discussed, albeit through a number of different mechanisms. DNA methylation, nucleosome repositioning and histone modification can all be effected as part of the transcription process and negatively impact promoter activity. Alternatively, transcription through enhancer (and perhaps other) elements can have a positive effect on gene expression, producing a permissive open chromatin environment. It isn’t all chromatin modification, though: Barlow lab favourite Airn gets a look in, and here transcription of Airn through the Igf2r promoter has a silencing effect that is not dependent on chromatin changes – the mechanism is unknown, but may involve physical obstruction of the promoter by RNA polymerase.
Returning to the question of function, it’s with this in mind the authors finish by laying out a number of ways to distinguish function of an ncRNA from function of its transcription – particularly useful as it isn’t yet clear how widely-applicable these kinds of regulatory mechanisms are. With significant and increasing interest in uncovering the ncRNA universe, we can almost certainly look forward to more examples in the future.
Written by Kester Jarvis, Senior Editor for BMC Biology.