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

Dominic G. Roy, Jocelyn Chen, Victoria Mamane, Eric H. Ma, Brejnev M. Muhire, Ryan D. Sheldon, Tatiana Shorstova, Rutger Koning, Radia M. Johnson, Ekaterina Esaulova, Kelsey S. Williams, Sebastian Hayes, Mya Steadman, Bozena Samborska, Amanda Swain, Audrey Daigneault, Victor Chubukov, Thomas P. Roddy, William Foulkes, J. Andrew PospisilikMarie Claude Bourgeois-Daigneault, Maxim N. Artyomov, Michael Witcher, Connie M. Krawczyk, Catherine Larochelle, Russell G. Jones

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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.

Original languageEnglish
Pages (from-to)250-266.e9
JournalCell metabolism
Volume31
Issue number2
DOIs
StatePublished - Feb 4 2020

Keywords

  • EAE
  • SAM
  • T cells
  • Th17 cells
  • histone methylation
  • inflammation
  • metabolism
  • methionine

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