The Arabidopsis Epitranscriptome

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Working with pea plants in his monastery garden, the Austrian monk Gregor Mendel discovered that they inherit from their parents, what we now know to be genes, which control how they grow. Like peas, the genes in the DNA of our chromosomes have the code for life. But what is that code exactly? DNA is comprised of long chains of chemicals of four different types: A, C, G and T. The genetic code is copied into a related molecule called RNA that is the messenger of this code. RNA is comprised of almost the same chemicals, A, C, and G, but U replaces T. Cellular machines called ribosomes, take the message and use it to build proteins corresponding to this code. Interestingly, the RNA chemicals can be altered, and by far the most common modification within the messenger RNA chain is m6A. Consequently, messenger RNA is effectively comprised of five different chemicals: A, C, G, U and m6A. You never heard of it? It is surprising how little attention it has had because if humans, flies or plants don't have it, they die. Recently, a human gene called FTO, which is linked to several human diseases, was found to encode a protein able to convert m6A back to A. This revealed that m6A levels in RNA could be controlled, and if this was disrupted, disease could result. It seems that m6A doesn't change the genetic code itself, but it does affect the message and so affects how the code is used in everyday life. This project is all about m6A in plants, but based on what we have done so far, it should tell us about animals and people as well.Like Mendel, our project results from discoveries we have made with plants. While studying a protein that naturally helps plants flower, Gordon Simpson's team discovered it controlled where messages end. Using a specially developed technique, they discovered that this protein is found close together with enzymes that make m6A. This made some sense because Rupert Fray, an RNA methylation expert, had previously shown that m6A is mostly found near the end of messages. So, using the same techniques to see what proteins were closely associated with the enzymes that make m6A, Gordon Simpson worked with Rupert Fray, and together, they discovered several proteins that were highly related across lots of different plants and animals, that helped these enzymes make m6A not only in plants but in humans as well.The aim of this project is to understand m6A a lot better by using plants. Plants are vital to our food and energy security so it is important that we know how they work. Because we can make mutant plants in the lab that still live but have altered levels of m6A, we can study them more simply and use that knowledge to try to understand why plants and animals use m6A in the message of their genetic code.First, we want to know which messages have m6A and where in the message is this found. We want to know if this changes in different situations such as in flowers compared to leaves or when the plant is stressed. Second, we want to know how m6A is made by the factors that help the enzymes we have found. Do they do it to all genes, or only some and only in specific parts of some messages? How do they talk about what they are doing to all the other parts of the cell that are making and reading the code as well? Third, we want to understand exactly what goes wrong when m6A is changed. What happens to individual messages? Finally, we'd like to begin to understand how the m6A code is read. Proteins with YTH domains apparently bind m6A, they are found in plants but we don't know what they do. We form a hugely experienced team in this area and we hope to learn very basic knowledge about the message of our genetic code. This work will provide state-of-the-art training for early career scientists working as a team on plants, genetics, RNA, proteins and computational analysis of large sequencing datasets - assembling the skills modern plant science needs to ensure future food and energy security.