Lurking in what used to be referred to as “junk DNA,” and beyond the realm of the well-known non-coding RNAs such as mRNA and tRNA, are non-coding sequences that are transcribed into RNAs with important epigenetic modulatory functions. Now in this special online collection in BioEssays (http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291521-1878/homepage/non_coding_rnas_virtual_ issue.htm) we bring together diverse corners of a rapidly expanding field of research.
Already it is becoming clear that certain miRNAs modulate the expression of RNAs coding for proteins cell cycle regulators, signalling pathway effectors and transcription factors that determine cell pluripotency, and cell fate, as discussed by Li and He 1. And from these observations it is a small conceptual step to assume that non-coding RNAs are also involved in cancer. Indeed, lncRNAs (long non-coding RNAs) are found highly expressed in solid tumours, and their mechanism of action, in general, appears to rely on their modification of chromatin via recruitment of chromatin remodelling complexes 2. Returning to their shorter cousins, miRNAs, it has been observed that the mammalian X-chromosome contains a disproportionately large number of sequences coding for miRNAs, and several of these have been shown to play roles in immunity and cancer. In a hypothesis piece, Pinheiro et al. 3 raise the possibility that the lesser immune response to infection mounted by males could be a result of males possessing only one X-chromosome. The other side of the coin is that females tend to suffer more autoimmune disease than males because (so it may be hypothesised) they have two X-chromosomes. The precise X-chromosome-encoded non-coding RNAs involved in autoimmunity have yet to be identified, but there is mounting support for the role of miRNAs in general in autoimmune disease. A strong recent candidate is an miRNA proposed to result from processing of a ribonucleoprotein-associated ‘Y RNA’ 4, the RNP of which (Ro RNP) is, itself, the target of the autoimmune response in systemic lupus erythematosus.
Beyond the immune system, a speculative article explores the roles of miRNAs in injury of the central nervous system 5: certain miRNAs are already recognised as key modulators of gene expression in processes involved with neuronal differentiation and maturation. But there is emerging evidence that defined miRNAs are consistently up- or down-regulated in ischaemia, traumatic brain injury and spinal cord injury, for example. Some are neurotoxic, whereas others are neuroprotective, hence opening a conceptual avenue to miRNA-based therapeutic intervention. And it is not only in CNS injury that non-coding RNAs play an important role in the brain: the mammalian brain and placenta manifest particularly high expression of imprinted genes, a phenomenon that is orchestrated by regulatory small-RNAs. In a hypothesis article, Labialle and Cavaillé propose that subclasses of these RNAs – recognised as “genomic parasites” – have contributed to the emergence of genomic imprinting by virtue of their occurrence in huge repeat arrays 6. In general, non-coding transcripts, including long non-coding RNA sequences, reside in juxtaposition with gene clusters in imprinted domains of chromosomes.
Regulatory non-coding RNAs are generated in a bewildering variety of ways via the processing of precursor transcripts, a newly hypothesised route being the fragmentation of small nucleolar RNAs (snoRNAs) into yet smaller, stable, RNAs 7. But regulatory non-coding RNAs need not only be encoded in the genome that they regulate: evidence is accumulating that external non-coding RNAs are very important for maintaining normal homeostasis. An obvious source is the food that we eat, and recently plant-derived RNAs have, indeed, been found circulating in the blood of the consumers 8.
And so, lastly, to the question of where, indeed, non-coding RNAs come from in the first place. It is likely that many miRNAs have arisen in response to the integration of retroviruses into the host genome: small complementary RNA sequences target the viral RNA for degradation or prevent it from being mobilised. Might they, therefore, have a deep evolutionary history in our unicellular ancestors? That is a very controversial claim, as Tarver et al. 9 make clear in an article that puts numerous miRNAs that suggest deep evolutionary origin to the test: most do not meet the criteria for miRNA annotation, suggesting that plants and animals did not acquire their respective miRNAs from a crown ancestor of eukaryotes after all. As for the rest of the non-coding RNA menagerie, it remains very fertile soil for hypothesis. Perhaps this question will be addressed in new articles that will regularly join our special collection in future.