Methylation of mRNA Molecules Dependent on Diet: Why Gene Regulation is Essential?

Two teams of researchers from the Switzerland-based University of Geneva, in collaboration with the Norwegian University of Science and Technology, recently discovered a diet-dependent mechanism for the regulation of RNA maturation.

According to a Phys.org report, the teams have focused on a particular type of chemical modification known as methylation of mRNA molecules in the tiny worm called Caenorhabditis elegans.

The researchers found that methylation on an mRNA's specific sequence results in its degradation and that this regulation mechanism is dependent on the worm's diet.

Specifically, sensitive to chemical modifications, messenger RNAs or mRNAs are molecules responsible for transferring the information encoded in the genome, allowing for the synthesis of proteins essential for the cells' functioning.

Findings of the study entitled "Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing" were published in the Cell journal.

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Methylation

A lot of steps are taking place before a DNA-encoded gene generates the equivalent protein. One of DNA's two strands is initially transcribed into RNA, which then goes through a number of processes which include splicing, before it goes through translation into a protein.

Such a process eliminates the unnecessary non-coding sequences or introns from the gene, leaving only the exons, the protein-coding sequences. This mature RNA form is also known as messenger RNA or mRNA.

On top of these processes, RNA, but also DNA molecules, can go through chemical modification called 'methylation.' This comprises adding a methyl group or CH3, which alters these molecules' fate minus modifying their sequence.

Deposited on the DNA or RNA in very particular places like Post-Its, methyl groups specify to the cell that a specific fate needs to be given to such molecules. RNA's methylation is essential. Specifically, mice minus RNA methylation are dying at an early embryonic phase.

Two teams at the UNIGE, one that worked on the regulation of RNA, and the other that specialized in the organization of DNA in the worm C. elegans or, roundworms and threadworms, as described by the College of Biological Sciences, have examined methylation's role in regulating gene expression.

Meanwhile, the laboratories of Florian Steiner and Ramesh Pillai, professors in the Department of Biology at the UNIGE Faculty of Science, for the first time, have exhibited that methylation at the end of the intron of a specific gene is blocking the splicing machinery. Essentially, the intron cannot be eliminated and the protein is not generated.

Self-Regulating Mechanism

Such gene, according to researcher and first author of the study, Mateusz Mendel, from the Department of Molecular Biology at the UNIGE Faculty of Science, whose mRNA is altered by methylation, is encoding for the enzyme that yields the methyl donor.

It is thus a self-regulating mechanism as the gene engaged in the production of key factors needed for the methylation process is itself regulated by methylation.

In addition, the said modification is dependent on the amount of nutrients the worms received. When there is an abundance of nutrients, the mRNA is methylated.

Gene splicing then, is blocked, and the methyl donors' level decreases, which restricts the number of probable methylation responses.

Researcher Kamila Delaney, from the Department of Molecular Biology at the UNIGE Faculty of Science said that when there are only a few nutrients, on the other hand, no methylation of the specific RNA of this gene takes place. Therefore, splicing doesn't get blocked and the methyl donors' synthesis increases.

Unusual Methylation Reactions

Elements that exist in the food offer the raw materials needed to produce methyl donors, so methylation-reliant splicing inhibition is putting a brake on its generation under circumstances of a rich diet.

Mendel explained, unusual methylation reactions, whether too little or too much, are the reasons for numerous diseases. He also said the cell has set up quite a sophisticated regulatory system to guarantee methylations' fair balance in the cell.

Methylation of mRNAs at these particular sequences was detected in by scientists which include former UNIGE professor, Ueli Schibler, in the 1970s.

It took four decades before scientists rediscovered in 2012 its essentiality in gene regulation. With this research, the Department of Molecular Biology scientists emphasized methylation's crucial role in the regulation of splicing, as well as in the reaction to environmental changes.

Related information on mRNA processing is shown on Catalyst University's YouTube video below: