The EPITRAN COST Action Consortium, COST Action CA16120
Epitranscriptomics, an expanding research area with great potential for biomedicine, biotechnology and crop production.
The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life.
However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease.
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.
This white paper was prepared by Prof Michael Jantsch (Vienna U.) with contributions from Epitran friends
International development: a wakeup call for Europe
Indeed, several countries have already recognized the potential impact of this new research area. For instance, the NIH in the USA has opened two specialized calls to explore the impact of the epitranscriptome on cancer (https://grants.nih.gov/grants/guide/pa-files/PA-16-177.html) and on brain development (https://grants.nih.gov/grants/guide/pa-files/PAR-17-152.html).
Similarly, Germany has one running and one starting joint research project on the Chemical Biology of Epigenetic Modifications and Chemical Biology of native Nucleic Acid Modifications, to name a few. The large interest in epitranscriptome research is also reflected by the number of reviews on this topic in the major scientific journals, now almost appearing on a monthly basis.
Thus the international development makes it clear that Epitranscriptome research is an emerging field with high potential. With some international and many national institutions rushing ahead, it is of utmost importance for European science development to establish coordinated funding at the European level.
A COST Action consortium on the Epitranscriptome termed “EPITRAN” (European Epitrancriptomics Network) has already been launched in 2017 with the aim to coordinate a synergistic network of Epitranscriptome research at the European level and to generate the awareness required to acquire European funding on this topic. It currently counts 26 member states and 60 management members. Already in its first year, three networking events are being organized.
The impact of a coordinated European Epitranscriptome network
Coordinated European Epitranscriptome research will affect health, wealth, nutrition and the environment within Europe. The dramatic increase in the number of diseases shown to be linked to changes in RNA modifications indicates major impact in virtually all fields of life and health science. Developing novel methods for the detection of modification patterns or tools for the manipulation of relevant modifications will provide the basis for the development of new diagnostics and therapeutics. Here we list the most prominent areas already known to be impacted by RNA modifications where an obvious profit from increased efforts in R&D is foreseeable: