Diet determines the placement of methylation signatures like post-its at specific sites on a messenger RNA (mRNA) marking the molecules for degradation, a new study on the microscopic model worm, Caenorhabditis elegans, reveals.

The findings of this collaborative study by scientists from the University of Geneva (UNIGE), Switzerland, and the Norwegian University of Science and Technology (NTNU) are published in an article titled, “Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing,” in the journal Cell.

Methylation of RNA is essential. Earlier studies show without RNA methylation mice die at an early embryonic stage.

In this study, the laboratories of Ramesh Pillai, PhD, and Florian Steiner, PhD, professors in the department of molecular biology at the UNIGE Faculty of Science, showed for the first time that methylation at the end of the intron of a particular gene (S-adenosylmethionine synthetase or SAM synthetase), blocks the splicing machinery—the process that removes unnecessary noncoding sequences (introns) from the gene, leaving only the protein-coding sequences (exons) in a mature messenger RNA.

The intron of the gene SAM synthetase, whose immature mRNA is specifically methylated at the tail-end of the intron, cannot be removed, and the functional protein cannot be produced.

“It is, therefore, a self-regulating mechanism since the gene involved in producing a key factor required for methylation is itself regulated by methylation!” explained Mateusz Mendel, a researcher in the department of molecular biology at the UNIGE Faculty of Science, and the first author of this study.

This methylation of the methyl-donating gene is dependent on the quantity of nutrients in the worms’ diet.

“When nutrients are abundant, the mRNA is methylated, gene splicing is blocked, and the level of methyl donors decreases, which limits the number of possible methylation reactions. On the other hand, when there are few nutrients, there is no methylation of the particular RNA of this gene, so splicing is not blocked and the synthesis of methyl donors increases,” said Kamila Delaney, PhD, a researcher in the department of molecular biology at the UNIGE Faculty of Science.

SAM levels are highly regulated in living organisms. This is accomplished by splicing regulation of the SAM synthetase RNA. Under high-SAM conditions, SAM synthetase pre-mRNA is methylated to directly inhibit splicing, intron retention, and decay of the mRNA. On the other hand, low SAM levels stimulate splicing.

The authors showed that although the mammalian SAM synthetase pre-mRNA is not regulated through this mechanism, splicing inhibition by methylation at the tail-end of the intron is conserved in mammals. The researchers also showed that the modification functions by physically preventing an essential component of the splicing machinery (U2AF35) from recognizing the tail-end of the intron’s splice site.

This study highlights the crucial role of methylation in regulating splicing, particularly in the response to changes in the environment, such as the availability of nutrients.

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