. 2020 Feb 4;31(2):250-266.e9.

doi: 10.1016/j.cmet.2020.01.006.

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

Dominic G Roy¹, Jocelyn Chen¹, Victoria Mamane², Eric H Ma³, Brejnev M Muhire⁴, Ryan D Sheldon⁴, Tatiana Shorstova⁵, Rutger Koning⁶, Radia M Johnson⁷, Ekaterina Esaulova⁸, Kelsey S Williams⁴, Sebastian Hayes⁹, Mya Steadman⁹, Bozena Samborska¹, Amanda Swain⁸, Audrey Daigneault⁶, Victor Chubukov⁹, Thomas P Roddy⁹, William Foulkes¹⁰, J Andrew Pospisilik¹¹, Marie-Claude Bourgeois-Daigneault¹², Maxim N Artyomov⁸, Michael Witcher⁵, Connie M Krawczyk¹³, Catherine Larochelle², Russell G Jones¹⁴

Affiliations

¹ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
² Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
³ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁴ Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁵ The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC, Canada.
⁶ Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada.
⁷ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
⁸ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University at St. Louis, St. Louis, MO 63110, USA.
⁹ Agios Pharmaceuticals, Cambridge, MA 02139, USA.
¹⁰ The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
¹¹ Metabolic and Nutritional Programming, Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹² Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
¹³ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
¹⁴ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: russell.jones@vai.org.

PMID: 32023446
DOI: 10.1016/j.cmet.2020.01.006

Free article

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

Dominic G Roy et al. Cell Metab. 2020.

Free article

. 2020 Feb 4;31(2):250-266.e9.

doi: 10.1016/j.cmet.2020.01.006.

Authors

Affiliations

¹ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
² Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
³ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁴ Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁵ The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC, Canada.
⁶ Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada.
⁷ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
⁸ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University at St. Louis, St. Louis, MO 63110, USA.
⁹ Agios Pharmaceuticals, Cambridge, MA 02139, USA.
¹⁰ The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
¹¹ Metabolic and Nutritional Programming, Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹² Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
¹³ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
¹⁴ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: russell.jones@vai.org.

PMID: 32023446
DOI: 10.1016/j.cmet.2020.01.006

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.

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Conflict of interest statement

Declaration of Interests 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.

Comment in

Dietary Methionine in T Cell Biology and Autoimmune Disease.
Tang S, Li X, Locasale JW. Tang S, et al. Cell Metab. 2020 Feb 4;31(2):211-212. doi: 10.1016/j.cmet.2020.01.007. Cell Metab. 2020. PMID: 32023442

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Publication types

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Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials