Long Noncoding RNAs: Past, Present, and Future
Abstract
Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years as a potentially new and crucial layer of biological regulation. lncRNAs of all kinds have been implicated in a range of developmental processes and diseases, but knowledge of the mechanisms by which they act is still surprisingly limited, and claims that almost the entirety of the mammalian genome is transcribed into functional noncoding transcripts remain controversial. At the same time, a small number of well-studied lncRNAs have given us important clues about the biology of these molecules, and a few key functional and mechanistic themes have begun to emerge, although the robustness of these models and classification schemes remains to be seen. Here, we review the current state of knowledge of the lncRNA field, discussing what is known about the genomic contexts, biological functions, and mechanisms of action of lncRNAs. We also reflect on how the recent interest in lncRNAs is deeply rooted in biology’s longstanding concern with the evolution and function of genomes.
THE past several years have witnessed a steep rise of interest in the study of lncRNAs. Almost on a weekly basis, it seems that a new lncRNA is found to be up- or downregulated in a particular disease, or a new class of noncoding transcripts is uncovered by a transcriptomic study, or a new article heralds a paradigm shift that lncRNAs will bring to our understanding of biology. Without a doubt, the advent of sensitive, high-throughput genomic technologies such as microarrays and next-generation sequencing (NGS) has resulted in an unprecedented ability to detect novel transcripts, the vast majority of which seem not to be derived from annotated protein-coding genes. Despite this explosion of data, however, surprisingly little is known about how lncRNAs function, how many different types of lncRNAs exist, or even whether most of them carry biological significance.
In this review, we focus on recently discovered lncRNAs of >200 nt, place these new discoveries in historical context, and outline areas where additional work is needed. The review does not cover “classic” ncRNAs such as ribosomal (r)RNAs, ribozymes, transfer (t)RNAs, small nuclear (sn)RNAs, small nucleolar (sno)RNAs, and telomere-associated RNAs (TERC, TERRA); nor does it cover small ncRNAs such as microRNAs (miRNAs), endogenous small interfering (endo-si)RNAs that participate in RNA interference (RNAi), and Piwi-associated (pi)RNAs. We refer readers to the many excellent recent reviews on these topics (Peculis 2000; Xiao et al. 2002; Henras et al. 2004; Okamura and Lai 2008; Kim et al. 2009; Feuerhahn et al. 2010; Blackburn and Collins 2011; Czech and Hannon 2011; Siomi et al. 2011). Although lncRNAs are found across many taxa, and many crucial discoveries have been made in plants, fungi, and invertebrates (Gelbart and Kuroda 2009; Au et al. 2011), we largely limit our discussion to mammalian examples, with occasional reference to lncRNAs of other taxa.
Acknowledgments
We thank members of the laboratory and T. R. Gregory for many helpful discussions, and we apologize to any of our colleagues whose work could not be cited here for space constraints. J.T.Y.K. was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada, and J.T.L. is supported by the National Institutes of Health (R01-GM090278). J.T.L. is an Investigator of the Howard Hughes Medical Institute.
Footnotes
Communicating editor: O. Hobert