Nutritional vitamin B12 regulates RAS/MAPK-mediated cell fate decisions through one-carbon metabolism

Ana Cristina Laranjeira, Simon Berger, Tea Kohlbrenner, Nadja R. Greter and Alex Hajnal ()
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Ana Cristina Laranjeira: University of Zurich
Simon Berger: University of Zurich
Tea Kohlbrenner: University of Zurich
Nadja R. Greter: University of Zurich
Alex Hajnal: University of Zurich

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway in C. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleoside metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.

Date: 2024
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DOI: 10.1038/s41467-024-52556-3

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