Functional Consequences Of The Plant Epitranscriptome

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DNA is comprised of long chains of "bases" of four different types: A, C, G and T. The information content of DNA resides primarily in the order in which these occur along its length. The genetic code is copied into a related molecule called RNA that is the messenger of this code. This messenger RNA (mRNA) moves out from the cell nucleus and is used by cellular machinery called ribosomes as a template on which to build proteins. RNA is comprised of almost the same bases, A, C, and G, but U replaces T. After a gene has been copied into mRNA, specific changes can be made to the bases of the mRNA itself. The most common modification within mRNA of both plants and animals is the addition of a small chemical "tag" to adenosines to make m6A in a process referred to as methylation. The frequency of m6A in mRNA is about 0.1-0.2%. This would correspond to an average of roughly once or twice per typical message, but we know that some messages contain several m6A sites whilst others contain none. The presence of the m6A "tag" does not change which amino acids are incorporated during translation and its function remained a mystery for more than 30 years. Ten years ago we showed that this modification was needed for normal developmental programmes in plants and yeast and other groups subsequently showed that this was also the case in animals. The reason for this is that the presence of m6A can affect how a mRNA is processed, when it is degraded and how many times it is used as a template for protein synthesis. However, the mechanisms by which m6A achieves this are still poorly understood.The methylation process is itself dynamic. The human fat mass and obesity associated gene, FTO, has been shown to encode a protein that can remove the "tag" and convert m6A back to A. FTO is linked to several serious human diseases, so understanding the function of m6A at a molecular level has become important for drug companies and researchers worldwide. Using plants as a model system, we have identified the group of enzymes that act together to put the "tag" on the mRNA and we have shown that the tag is usually placed near the end of mRNA. These enzymes and features of mRNA methylation were subsequently found to be highly conserved between plants and animals. Thus, experiments in plants that are much simpler to perform than in mammals can reveal fundamental principles that are likely to operate in humans also.Plants that we have engineered to have low levels of m6A are small, weak and have specific developmental defects. By randomly mutating thousands of seeds from these plants, we found some plants that grew normally, even though they still had very low m6A levels. One of the mutations that restores normal growth is in a gene that encodes a protein that forms part of the ribosome. This ribosomal protein is needed to restart or continue translation of mRNAs with certain structures, both in plants and in some human viruses. The aim of this project is to understand the way in which m6A regulates how some mRNAs are translated by ribosomes. This is important because it is likely a conserved process that underlies m6A function in human processes too. We will also identify the mutations in other genes that allow our low m6A plants to grow normally, we anticipate that similar gene functions will also be present in human and that insights gained from our plant model system will continue to inform the research field.