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Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming

Roy DG, Chen J, Mamane V, Ma EH, Muhire BM, Sheldon RD, Shorstova T, Koning R, Johnson RM, Esaulova E, Williams KS, Hayes S, Steadman M, Samborska B, Swain A, Daigneault A, Chubukov V, Roddy TP, Foulkes W, Pospisilik JA, Bourgeois-Daigneault MC, Artyomov MN, Witcher M, Krawczyk CM, Larochelle C, Jones RG (2020) Cell Metab. 2020 Feb;31(2): 250-266.e9. doi: 10.1016/j.cmet.2020.01.006.  

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Abstract:

Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Here we identify methionine as a key nutrient affecting epigenetic reprogramming in CD4+ T helper (Th) cells.

Using metabolomics, we showed that 
methionine is rapidly taken up by activated T cells and serves as the major substrate for biosynthesis of the universal methyl donor S-adenosyl-L-methionine (SAM). Methionine was required to maintain intracellular SAM pools in T cells. Methionine restriction reduced histone H3K4 methylation (H3K4me3) at the promoter regions of key genes involved in Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset.

Our data identify 
methionine as a key nutritional factor shaping Th cell proliferation and function in part through regulation of histone methylation.

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