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 Vaeth; John Ussher; Boudewijn M.T. Burgering; Paul J. Coffer

doi:10.1016/j.celrep.2023.112583

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	112583
Journal	Cell Reports
Volume	42
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2023.112583
Publication status	Published - 27 Jun 2023
Externally published	Yes

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Publisher Copyright:
© 2023 The Author(s)

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Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activationFinal published version, 4.92 MBLicence: CC BY-NC-ND

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Mocholi, E., Russo, L., Gopal, K., Ramstead, A. G., Hochrein, S. M., Vos, H. R., Geeven, G., Adegoke, A. O., Hoekstra, A., van Es, R. M., Pittol, J. R., Vastert, S., Rutter, J., Radstake, T., van Loosdregt, J., Berkers, C., Mokry, M., Anderson, C. C., O'Connell, R. M., ... Coffer, P. J. (2023). Pyruvate metabolism controls chromatin remodeling during CD4⁺ T cell activation. Cell Reports, 42(6), Article 112583. https://doi.org/10.1016/j.celrep.2023.112583

@article{c945a868162d4eb9a71eca726633f521,

title = "Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jun,

day = "27",

doi = "10.1016/j.celrep.2023.112583",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

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Mocholi, E, Russo, L, Gopal, K, Ramstead, AG, Hochrein, SM, Vos, HR, Geeven, G, Adegoke, AO, Hoekstra, A, van Es, RM, Pittol, JR, Vastert, S, Rutter, J, Radstake, T, van Loosdregt, J, Berkers, C, Mokry, M, Anderson, CC, O'Connell, RM, Vaeth, M, Ussher, J, Burgering, BMT & Coffer, PJ 2023, 'Pyruvate metabolism controls chromatin remodeling during CD4⁺ T cell activation', Cell Reports, vol. 42, no. 6, 112583. https://doi.org/10.1016/j.celrep.2023.112583

TY - JOUR

T1 - Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation

AU - Mocholi, Enric

AU - Russo, Laura

AU - Gopal, Keshav

AU - Ramstead, Andrew G.

AU - Hochrein, Sophia M.

AU - Vos, Harmjan R.

AU - Geeven, Geert

AU - Adegoke, Adeolu O.

AU - Hoekstra, Anna

AU - van Es, Robert M.

AU - Pittol, Jose Ramos

AU - Vastert, Sebastian

AU - Rutter, Jared

AU - Radstake, Timothy

AU - van Loosdregt, Jorg

AU - Berkers, Celia

AU - Mokry, Michal

AU - Anderson, Colin C.

AU - O'Connell, Ryan M.

AU - Vaeth, Martin

AU - Ussher, John

AU - Burgering, Boudewijn M.T.

AU - Coffer, Paul J.

PY - 2023/6/27

Y1 - 2023/6/27

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85160779504

U2 - 10.1016/j.celrep.2023.112583

DO - 10.1016/j.celrep.2023.112583

M3 - Article

C2 - 37267106

AN - SCOPUS:85160779504

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 112583

ER -

Pyruvate metabolism controls chromatin remodeling during CD4⁺ T cell activation

Abstract

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