Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation

Enric Mocholi, Laura Russo, Keshav Gopal, Andrew G Ramstead, Sophia M Hochrein, Harmjan R Vos, Geert Geeven, Adeolu O Adegoke, Anna Hoekstra, Robert M van Es, Jose Ramos Pittol, Sebastian Vastert, Jared Rutter, Timothy Radstake, Jorg van Loosdregt, Celia Berkers, Michal Mokry, Colin C Anderson, Ryan M O'Connell, Martin VaethJohn Ussher, Boudewijn M T Burgering, Paul J Coffer

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Abstract

Upon antigen-specific T cell receptor (TCR) engagement, human CD4 + T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4 + T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.

Original languageEnglish
Article number112583
Pages (from-to)1-24
JournalCell Reports
Volume42
Issue number6
Early online date1 Jun 2023
DOIs
Publication statusPublished - 27 Jun 2023

Keywords

  • citrate
  • CP: Metabolism
  • epigenetics
  • epigenome remodeling
  • glucose metabolism
  • glycolysis
  • histone acetylation
  • nuclear metabolism
  • pyruvate
  • pyruvate dehydrogenase
  • T cell

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