Not as Non-Coding as We Once Thought: When Non-Coding RNAs Translate into Small Peptides

What biologists have long referred to as “non-coding RNA” may not be as non-coding as previously thought. A new review article by researchers from the Laboratory of Regulation of Gene Expression at the IMIC CAS, published in The EMBO Journal, focuses on so-called long non-coding RNAs (lncRNAs). Emerging evidence shows that these RNAs can serve as templates for the production of small yet biologically important proteins that contribute to the regulation of metabolism, immunity, organismal development, and disease.

Genetic information is transcribed from deoxyribonucleic acid (DNA) into ribonucleic acid (RNA) and subsequently translated into protein. For a long time, biology was guided by a simple rule: genes encoding proteins were considered the important part of the genome, numbering roughly 20,000 in humans, while much of the remaining genome was thought to produce RNA molecules that do not encode proteins. Over the last two decades, however, it has become clear that reality is far more complex.

The human genome contains tens of thousands of so-called long non-coding RNA (lncRNA) genes, many of whose functions remain largely mysterious. Some of these molecules are capable of producing very short peptides or microproteins, typically consisting of only a few dozen amino acids. These molecules are much smaller than conventional proteins and are often produced only in specific cell types and under particular conditions. As a result, many of them have been discovered only within the last decade. It is a bit like searching for a single short sentence in a library containing millions of books.

Thanks to advances in bioinformatics and experimental methods, the hidden translational potential of lncRNAs is gradually coming to light. This is reflected in the growing number of publications reporting exciting discoveries made within the relatively short span of the last 10 to 20 years.

Small Proteins with a Big Impact

In this comprehensive review article, a five-member team of researchers led by Leoš S. Valášek summarizes, among other things, the functions in which micropeptides derived from lncRNAs participate within the cell. These small proteins are involved in regulating a wide range of key biological processes, such as energy metabolism, cell signaling, DNA repair and regulation, immune system, nervous system development, muscle development, stress responses, cell division, and the onset and spread of cancer. The authors also mentioned several interesting examples in which peptides contribute to the regulation of cellular processes not only on their own but in collaboration with their RNA template.

The discovery of coding regions in RNA—which were originally considered non-coding—represents another step in reshaping our understanding of genetic information. It is becoming increasingly clear that there is no sharp boundary between classical protein-coding genes and non-coding regions of the genome. Human cells may contain a hidden world of hundreds of unknown small proteins whose biological significance is only beginning to be uncovered.

Review articles are primarily written by renowned researchers or specialists with extensive knowledge in a given field. The aim is not to conduct new experiments, but to summarize and evaluate previously published research.

PUBLICATION

Valášek LS, Brázdovič F, Trčka F, Mohammad MP, Roithová A. The identity crisis of cryptic lncRNAs: when noncoding RNAs translate into small peptides, The EMBO Journal (2026); doi: 10.1038/s44318-026-00826-9.