Particularly sensitive to chemical modifications, messenger RNAs (mRNAs) are molecules responsible for transmitting the information encoded in our genome, allowing the synthesis of proteins, necessary for the functioning of our cells. Two teams from the University of Geneva (UNIGE), Switzerland, in collaboration with the Norwegian University of Science and Technology (NTNU), focused on a specific type of chemical modification – called methylation – of mRNA molecules in the little worm Caenorhabditis elegans. They found that methylation on a particular sequence of an mRNA leads to its degradation and that this control mechanism depends on the diet of the worm. These results are to be read in the newspaper Cell.
Several steps take place before a gene encoded by DNA produces the corresponding protein. One of the two strands of DNA is first transcribed into RNA, which then undergoes several processes, including splicing, before being translated into protein. This process removes unnecessary non-coding sequences (introns) from the gene, leaving only the protein-coding sequences (exons). This mature form of RNA is called messenger RNA (mRNA).
A “post-it” to block protein synthesis
In addition to these processes, RNA – but also DNA molecules – can undergo a chemical modification: methylation. This consists in adding a methyl group (CH3) which makes it possible to modify the fate of these molecules without altering their sequence. Deposited on the RNA or the DNA in very specific places like the “post-its”, the methyl groups indicate to the cell that a particular destiny must be given to these molecules. RNA methylation is essential: mice without RNA methylation die at an early embryonic stage.
Two neighboring teams at UNIGE, one working on RNA regulation and the other specialized in DNA organization in worms C. elegans, studied the role of methylation in the control of gene expression. The laboratories of Ramesh Pillai and Florian Steiner, professors in the Department of Molecular Biology of the Faculty of Sciences at UNIGE, have shown for the first time that methylation at the end of the intron of a particular gene blocks the machinery splicing. The intron cannot be removed and the protein is not produced.
Fine-grained regulations to ensure a fair balance
This gene, whose mRNA is modified by methylation, codes for the enzyme that produces the methyl donor. “It is therefore a self-regulatory mechanism since the gene involved in the production of a key factor necessary for methylation is itself regulated by methylation!”, Explains Mateusz Mendel, researcher at the Department of Molecular Biology of the Faculty of Sciences of UNIGE, and the first author of this study.
In addition, this modification depends on the amount of nutrients received by the worms. “When nutrients are abundant, mRNA is methylated, gene splicing is blocked and the level of methyl donors decreases, which limits the number of possible methylation reactions. In contrast, when there is little nutrients, there is no methylation of the particular RNA of this gene, so splicing is not blocked and the synthesis of methyl donors increases ”, reports Kamila Delaney, researcher in the Department of Molecular Biology of the Faculty of UNIGE sciences.The elements present in the food provide the raw materials necessary for the production of the methyl donor, so that the inhibition of splicing dependent on methylation puts a brake on its production under conditions of rich diet. “Aberrant methylation reactions – too much or not enough – are the cause of many diseases. The cell has set up this very sophisticated regulatory system to ensure a fair balance of methylations in the cell”, sums up Mateusz Mendel.
Methylation of mRNAs at the level of these specific sequences was discovered in the 1970s by scientists, including Ueli Schibler, a former professor at UNIGE, before being forgotten. It took 40 years before researchers rediscovered its importance in gene regulation in 2012. With this study, scientists in the Department of Molecular Biology highlight the crucial role of methylation in controlling splicing and in splicing. response to environmental changes.
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