LAUSR

How do you measure the success of a venture? One simple method is to count the number of participants involved. Using this criterion, the COST action CA16120 EPITRAN, which focuses on the research of the epitranscriptome, has been an astounding success, way beyond any initial expectations. Currently, there are approximately 105 research groups located in 30 countries within this network. The COST EPITRAN action has provided a unique and valuable networking opportunity where European groups who are new in the field of epitranscriptomics can benefit from the experience and knowledge of experts. In addition, COST EPITRAN has offered valuable training opportunities to students within the network. However, COST EPITRAN has done something more significant; it has established a strong European alliance of groups that study various RNA modifications in different model systems thereby promoting the field of epitranscriptomics and together petition the EU Commission and Parliament to support this dynamic field of research. The networking activities established through this COST action have also initiated national research networks and panEuropean collaborations. The current pandemic illustrates the importance of this field of research; the introduction of RNA modifications into the mRNA of the Covid19 vaccine was key to its success, as it prevented the innate immune response from being activated which would have led to degradation of the vaccine mRNA and reduced virus coat protein expression. But this pandemic also has a cautionary lesson. For too long funding bodies have had little interest in supporting research on RNA modifications as these were considered of little economic impact or health relevance. Funding priorities were elsewhere, on cures for cancer and other ‘priority’ diseases. An analogy to this situation would be the Renaissance, prior to which artists repeatedly painted the Madonna and similar themes, as their patron, the Church demanded it. Only with the advent of wealthy benefactors did artists have the freedom to create exceptional works of art. Scientific research should be liberated in a similar manner and not be constrained by political objectives, however well intentioned, that hamper its growth and creativity. One has to remember that scientific breakthroughs come from the leading edge and are mostly serendipitous. We cannot predict what piece of novel research will be instrumental in fighting the next pandemic or indeed curing cancer. With the limelight currently on RNA modification, one should take stock; where is the field at the moment and where is it going? In 1957, the first modified RNA base isolated from bulk yeast RNA was pseudouridine (ψ). Currently, a total of approximately 170 RNA modifications are known to occur in one or more types of RNA or divisions of life. In 1974 two groups described the occurrence of N(6)methyladenosine (mA) in mRNA. It is the most abundant RNA modification occurring internally in mRNA. The mA field lay dormant for many years until the group of Rupert Fray in 2008 described its occurrence in mRNA isolated from Arabidopsis. However, it was in 2012 when the field finally took off with the development of antibodies, next-generation sequencing, and mass spectrometry, which allowed the mapping of mA in mRNA. Many fell in love with this dynamic field where there are ‘writers, erasers and readers’ of this modification. It was obvious from the start that mA is absolutely essential. However, the outcome of the modification is difficult to predict as it depends on the readers of the modification and their expression profile in particular cell lines and tissues. Sometimes the modification can have completely opposite outcomes on different mRNAs for example it can increase or decrease the stability of a particular mRNA. The other very abundant modification occurring in mRNA is adenosine deamination to inosine. The enzymatic activity was first identified in 1987 and initially thought to be RNA helicases unwinding double-stranded (ds)RNA. However, subsequent research demonstrated that it was deamination of adenosine to inosine that caused the unwinding of the dsRNA as the inosine no longer forms a Watson Crick basepair with uracil. Inosine can be read as guanosine by reverse transcriptase and the translation machinery, thus it can result in recoding with a different amino acid being inserted at a specific position. For this historic reason, it was called RNA editing; however, as it is now evident that inosine in vertebrate mRNA rarely results in recoding, the term RNA editing seems rather moot and inosine often acts like other RNA modifications. The first major site-specific editing event to be described ̧ in the GRIA2 transcript encoding glutamate AMPA receptor subunit 2 (GRIA2), caused the conversion of glutamine to arginine (Q/R) at the critical pore position. The GRIA2 Q/R site is edited to 100% and is essential as it confers calcium impermeability on AMPA receptors. Unfortunately, editing at this critical Q/R site caused a major problem for the field as for many years researchers were convinced that many other essential editing positions resulting in recoding would be uncovered. Alas, RNA editing at the Q/R site is an exception and despite the work of the groups of Levanon and Eisenberg, it took approximately 20 years for researchers to appreciate that editing of transcripts encoding repetitive elements is also essential. A fundamental function of inosine in RNA is to help the cell to discriminate between self and non-self dsRNA. RNA BIOLOGY 2021, VOL. 18, NO. S1, 1–3 https://doi.org/10.1080/15476286.2021.1982121