Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation
Mocholi, Enric; Russo, Laura; Gopal, Keshav; Ramstead, Andrew G; Hochrein, Sophia M; Vos, Harmjan R; Geeven, Geert; Adegoke, Adeolu O; Hoekstra, Anna; van Es, Robert M; Pittol, Jose Ramos; Vastert, Sebastian; Rutter, Jared; Radstake, Timothy; van Loosdregt, Jorg; Berkers, Celia; Mokry, Michal; Anderson, Colin C; O'Connell, Ryan M; Vaeth, Martin; Ussher, John; Burgering, Boudewijn M T; Coffer, Paul J
(2023) Cell Reports, volume 42, issue 6, pp. 1 - 24
(Article)
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,
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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.
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Keywords: citrate, CP: Metabolism, epigenetics, epigenome remodeling, glucose metabolism, glycolysis, histone acetylation, nuclear metabolism, pyruvate, pyruvate dehydrogenase, T cell, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: We are grateful to all the authors of this paper for their contributions and significant effort in completing and publishing this research. We would like to extend a special thank you to J.U. and K.G. (Alberta University) for their assistance in generating the Pdca1-KO mice, which were essential to the study’s success. We would like to express our gratitude to M.V. at the Würzburg Institute for generously providing us with the ACLY KO needed to validate our hypothesis. We would also like to thank H.R.V. and R.M.v.E. from the proteomic facility of the UMC for their scientific discussions and for their assistance with the challenging experiments involving carbon tracing of heavy carbons from glucose that are incorporated into histone modifications. Their expertise and exceptional problem-solving skills were instrumental in the success of this study. We would also like to express our gratitude to R.M.O. from Utah University for providing us with valuable data from the MPC1-KO mice. In conclusion, we would also like to extend our gratitude to G.G. and M.M. for their invaluable assistance with the RNA-seq and ChIP-seq analyses performed in this study. Finally, we would like to thank all members of the Coffer Lab for their valuable discussions concerning this work. This work is supported by the Stichting WKZ Foundation (2016) and ReumaNetherlands ( NR 18- 01-401 ). Funding Information: We are grateful to all the authors of this paper for their contributions and significant effort in completing and publishing this research. We would like to extend a special thank you to J.U. and K.G. (Alberta University) for their assistance in generating the Pdca1-KO mice, which were essential to the study's success. We would like to express our gratitude to M.V. at the Würzburg Institute for generously providing us with the ACLY KO needed to validate our hypothesis. We would also like to thank H.R.V. and R.M.v.E. from the proteomic facility of the UMC for their scientific discussions and for their assistance with the challenging experiments involving carbon tracing of heavy carbons from glucose that are incorporated into histone modifications. Their expertise and exceptional problem-solving skills were instrumental in the success of this study. We would also like to express our gratitude to R.M.O. from Utah University for providing us with valuable data from the MPC1-KO mice. In conclusion, we would also like to extend our gratitude to G.G. and M.M. for their invaluable assistance with the RNA-seq and ChIP-seq analyses performed in this study. Finally, we would like to thank all members of the Coffer Lab for their valuable discussions concerning this work. This work is supported by the Stichting WKZ Foundation (2016) and ReumaNetherlands (NR 18- 01-401). The experiments were mainly performed by E.M. with the assistance of L.R. J.U. and K.G. contributed by generating the Pdha1-KO mice and were involved in some experiments using this mouse model. A.G.R. J.R. and R.M.O. conducted all the experiments with the MPC1 KO mice. The metabolomics studies were conducted by S.M.H. and C.B. while H.R.V. and R.M.v.E. performed carbon tracing of heavy carbons from glucose incorporated into histone modifications. G.G. and M.M. analyzed the RNA-seq and ChIP-seq data. A.O.A. and C.C.A. conducted the EAE model with the Pdha1 mouse model, which was not included in the final version of the paper. During the study, S.M.H. and M.V. played a crucial role by providing us with the ACLY KO and conducting some of the experiments with this mouse model. The scientific discussions led by J.R. S.V. T.R. J.v.L. and B.M.T.B. were highly valuable in generating hypotheses and improving the overall experimental design. The study was designed and written by E.M. and P.J.C. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2023 The Author(s)
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