Abstract
In the early years of Molecular Biology, the role of RNA was largely considered to be the transmission of the genetic information stored in the DNA into polypeptides. Three major types of RNA engaged in these processes were known: messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA). However, within the last half century our knowledge about RNA classes, abundance and diversity of functions has increased dramatically. The discovery that the ribosome is essentially a ribozyme 1, 2 especially brought the central role of RNA for cellular life into the spotlight. The turn of the millennium was also the time of another far‐reaching realization, that of the pervasiveness of small RNA‐dependent regulation of gene expression 3. Within the decade that followed, RNAs were found in essentially all regulatory layers of gene expression, from the epigenetic layer at the top of the gene expression cascade 4, 5 to the most distal translation layer 6. Much of this rapid transition was enabled by sequencing technologies that were developed in the wake of the human genome project. Coupled with ingenious protocols for isolating RNAs of various sizes and molecular properties (e.g. 7) and computational methods to annotate various classes of small RNAs 8, the set of regulatory RNAs has expanded and diversified rapidly. We now know that < 2% of the human genome contains protein‐coding genes, whereas 80% is transcribed into noncoding RNAs (ncRNAs), classified based on their size into small and long noncoding RNAs (lncRNAs). Small ncRNAs include the highly investigated microRNAs (miRNAs) that were found to be increased in various cancer types where they exhibit pro‐oncogenic activity 9. LncRNAs are long (> 200 nucleotides) transcripts that functionally contribute to the control of cell differentiation and maintenance of cell identity. Notably, as most (~ 90%) of disease‐associated single nucleotide polymorphisms are located in gene regulatory or intergenic regions, long‐intergenic ncRNAs (lincRNAs) in particular may have pivotal impact for the development of personalized medicine therapies in the future10. Whether small or long, ncRNAs often bear domains enabling direct and specific interactions with other RNAs, forming RNA‐RNA hybrids that participate in the control of gene expression and biogenesis of RNAs 11.