Long noncoding RNA (lncRNA) research has exploded in recent years, indicating potential roles for these molecules in regulation of gene expression at the transcriptional, post-transcriptional and epigenetic levels. Recently, an even greater level of complexity was introduced with the realization that some RNAs currently classified as lncRNAs are apparently not noncoding after all. While they’re not full protein-coding RNAs like messenger RNA, they do code for nonclassical small bioactive peptides called micropeptides. The micropeptides originating from lncRNA can perform important roles in the body, meaning that revisiting the classification of many currently “noncoding” RNAs may hold the key to more biologically relevant discoveries.
Long noncoding RNAs are, as the name suggests, longer than small regulatory RNAs like microRNAs, siRNAs and piRNAs. Defined as noncoding transcripts >200 nucleotides in length, lncRNA is abundant in humans and shows low conservation across species, in contrast to other small noncoding RNAs like microRNA. Our understanding of their function is still in its infancy, as less than 300 lncRNAs are currently functionally annotated in the online lncRNA database, 183 of which are human. Check out the recorded webinar on lncRNA as biomarkers to learn more
Micropeptides, in contrast to other small bioactive peptides, aren’t enzymatically cleaved from precursor proteins, and they also don’t contain the signaling sequence at the N terminus that directs other small bioactive peptides toward the secretory pathway. Instead, after being translated, they go directly into the cytoplasm. These types of small peptides have been studied in both plants and animals, and the search is on for small open reading frames that could code for them (1).
lncRNAs have been an intriguing area of investigation for micropeptides, due to the presence of small open reading frames and high ribosomal occupancy, but ribosomal occupancy doesn’t always equal translation. And even if a small ORF is translated, its peptide may not be functional (1). These limitations on in silico analysis and ribosomal profiling mean that greater investigation is required to determine which lncRNAs may contain coding regions for micropeptides.
In the last 2 years, studies have identified functionally important micropeptides translated from lncRNAs. Anderson and colleagues, publishing in Cell in 2015, described a lncRNA that coded for myoregulin (MLN), a 46-amino acid micropeptide that reduces muscle performance by inhibiting the calcium ATPase SERCA in muscle cells. MLN was derived from a lncRNA called LINC00948 in human and AK009351 in mouse (2). This year, some of the same authors as well as others have published a new paper in Science with similar results – they describe another lncRNA-derived micropeptide, DWORF, that activates SERCA to boost muscle performance. The lncRNA responsible for this micropeptide is called LOC100507537 in human and NONMMUG026737 in mouse (3). Their findings lend support to the role of some RNAs that are currently classified as noncoding in producing micropeptides with biological impact.
These findings add a new layer of complexity to our understanding of the functional areas of the human genome. What do they mean for future lncRNA research? Potentially, quite a lot. It’s no longer a given that RNAs classified as lncRNA are purely noncoding. In light of these discoveries, it will be important in the future to not only study the potential of lncRNA as noncoding regulatory RNAs, but also to investigate the potential coding ability of any small ORFs in these RNAs to determine whether they are hiding functional peptides.
Want to know more about lncRNA research? Check out our recorded webinar on the role of lncRNAs in cancer and regulation of microRNA expression. View the webinar here!
- 1. Crappé, J. et al. (2014) Little things make big things happen: a summary of micropeptide encoding genes. EuPA Open Proteomics 3, 128. Link
- 2. Anderson, D.M. et al. (2015) A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160, 595. Link
- 3. Nelson, B.R. et al. (2016) A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351, 271. Link