In contrast to DNA modifications, nucleotide modifications in RNA are far more diverse and abundant, with more than 140 modifications known to date. Modifications in RNA can change the coding of messenger RNAs (mRNAs) and therefore diversify genetic information. Most RNA modifications cannot be identified by traditional sequencing methods. Thus, despite huge investments in RNA Seq, we are still missing an important layer of cellular diversity. Modifications can also affect the processing/splicing, localization, stability, turnover, or translation of mRNAs. Importantly, RNA modifications can be applied transiently, allowing a fast response to changing cellular or environmental conditions. Lastly, similar to the findings of epigenetics research in DNA, groups of proteins have been identified that specifically recognize and bind modified nucleotides thereby affecting the fate of RNA.
Not all RNA modifications can be synthesized by the organisms in which they are found, but can be delivered as a nutrient by the microbiome, therefore regulating host-microbe interactions. Revealing the mechanisms of specific uptake of these chemical “precursors” and their installation as RNA modifications will not only provide information on the metabolism of these substances and cellular pathways, but likely reveal new diseases linked to the machineries involved. RNA modification can also be involved in cell-to-cell horizontal transfer of information mediated by extracellular vesicles.
Most importantly, changes in RNA modifications have been recognized as being the cause of several diseases ranging from immune disorders, over neuromuscular defects, to cancer. Already this knowledge is used and methods that aim at redirecting specific modifications to clinically relevant sites are being tested.
Thus, today, 30 years after the advent of molecular research in epigenetics, we anticipate a similar, if not bigger explosion in Epitranscriptome research with even a larger impact on biomedical, pharmaceutical, livestock, and agricultural developments.