@article{da22b60f48a94372bf8476e046d0c007,
title = "Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming",
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.",
keywords = "EAE, SAM, T cells, Th17 cells, histone methylation, inflammation, metabolism, methionine",
author = "Roy, {Dominic G.} and Jocelyn Chen and Victoria Mamane and Ma, {Eric H.} and Muhire, {Brejnev M.} and Sheldon, {Ryan D.} and Tatiana Shorstova and Rutger Koning and Johnson, {Radia M.} and Ekaterina Esaulova and Williams, {Kelsey S.} and Sebastian Hayes and Mya Steadman and Bozena Samborska and Amanda Swain and Audrey Daigneault and Victor Chubukov and Roddy, {Thomas P.} and William Foulkes and Pospisilik, {J. Andrew} and Bourgeois-Daigneault, {Marie Claude} and Artyomov, {Maxim N.} and Michael Witcher and Krawczyk, {Connie M.} and Catherine Larochelle and Jones, {Russell G.}",
note = "Funding Information: We thank members of the Jones, Krawczyk, Pospisilik, and Witcher laboratories and colleagues at Agios Pharmaceuticals for advice regarding the manuscript. We acknowledge technical assistance from the VAI Metabolomics, Flow Cytometry and Bioinformatics and Biostatistics core facilities, the McGill-GCRC Metabolomics and Flow Cytometry core facilities, and the CRCHUM flow cytometry platform. The GCRC Metabolomics Core Facility is supported by grants from the Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), and Terry Fox Research Institute (TFRI). We acknowledge salary support from the McGill Integrated Cancer Research Training Program (to E.H.M.), the Multiple Sclerosis Society of Canada, and the Fonds de la Recherche du Qu{\'e}bec – Sant{\'e} (FRQS, to E.H.M. D.G.R. M.-C.B.-D. and C.L.; FRQS-MSSOC studentship to V.M.). This research has been supported by grants from the Multiple Sclerosis Society of Canada (to C.L.) and CIHR (MOP-399061 to M.W. and MOP-142259 to R.G.J.). Experimental design and execution were conducted by D.G.R. J.C. E.H.M. T.S. V.M. R.K. S.H. M.S. B.S. A.D. M.-C.B.-D. M.W. C.L. and R.G.J. Bioinformatics and data analysis were conducted by B.M.M. E.E. K.S.W. R.M.J. A.S. R.D.S. and M.N.A. Data interpretation was performed by D.G.R. J.C. E.H.M. V.M. M.S. V.C. T.P.R. J.A.P. M.-C.B.-D. M.W. C.M.K. C.L. and R.G.J. Research supervision was carried out by W.F. M.W. C.M.K. C.L. and R.G.J. The manuscript was written and edited by D.G.R. J.C. E.H.M. K.S.W. C.L. and R.G.J. S.H. V.C. and T.P.R. are employees and shareholders of Agios Pharmaceuticals. R.M.J. is an employee of Genentech. M.S. is an employee of Rheos Therapeutics. R.G.J. is a consultant to Agios Pharmaceuticals and is a shareholder and member of the scientific advisory board of Immunomet Therapeutics. Funding Information: We thank members of the Jones, Krawczyk, Pospisilik, and Witcher laboratories and colleagues at Agios Pharmaceuticals for advice regarding the manuscript. We acknowledge technical assistance from the VAI Metabolomics, Flow Cytometry and Bioinformatics and Biostatistics core facilities, the McGill-GCRC Metabolomics and Flow Cytometry core facilities, and the CRCHUM flow cytometry platform. The GCRC Metabolomics Core Facility is supported by grants from the Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), and Terry Fox Research Institute (TFRI). We acknowledge salary support from the McGill Integrated Cancer Research Training Program (to E.H.M.), the Multiple Sclerosis Society of Canada , and the Fonds de la Recherche du Qu{\'e}bec – Sant{\'e} (FRQS, to E.H.M., D.G.R., M.-C.B.-D., and C.L.; FRQS-MSSOC studentship to V.M.). This research has been supported by grants from the Multiple Sclerosis Society of Canada (to C.L.) and CIHR ( MOP-399061 to M.W. and MOP-142259 to R.G.J.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = feb,
day = "4",
doi = "10.1016/j.cmet.2020.01.006",
language = "English",
volume = "31",
pages = "250--266.e9",
journal = "Cell Metabolism",
issn = "1550-4131",
number = "2",
}