Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites

Anna-Sophia Egger; Eva Rauch; Suraj Sharma; Tobias Kipura; Madlen Hotze; Thomas Mair; Alina Hohenegg; Philipp Kobler; Ines Heiland; Marcel Kwiatkowski

doi:10.1016/j.molmet.2024.102032

Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites

Mol Metab. 2024 Sep 19:90:102032. doi: 10.1016/j.molmet.2024.102032. Online ahead of print.

Authors

Affiliations

¹ Department of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
² Department of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
³ Department of Biomedicine, University of Bergen, 5020 Bergen, Norway; Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, 5021, Norway.
⁴ Department of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria; Section / Core Facility Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Department of Biomedicine, University of Bergen, 5020 Bergen, Norway; Department of Arctic and Marine Biology, UiT the Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: ines.heiland@uit.no.
⁶ Department of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria. Electronic address: marcel.kwiatkowski@uibk.ac.at.

Abstract

Objectives: Histone acetylation is an important epigenetic modification that regulates various biological processes and cell homeostasis. Acetyl-CoA, a hub molecule of metabolism, is the substrate for histone acetylation, thus linking metabolism with epigenetic regulation. However, still relatively little is known about the dynamics of histone acetylation and its dependence on metabolic processes, due to the lack of integrated methods that can capture site-specific histone acetylation and deacetylation reactions together with the dynamics of acetyl-CoA synthesis.

Methods: In this study, we present a novel proteo-metabo-flux approach that combines mass spectrometry-based metabolic flux analysis of acetyl-CoA and histone acetylation with computational modelling. We developed a mathematical model to describe metabolic label incorporation into acetyl-CoA and histone acetylation based on experimentally measured relative abundances.

Results: We demonstrate that our approach is able to determine acetyl-CoA synthesis dynamics and site-specific histone acetylation and deacetylation reaction rate constants, and that consideration of the metabolically labelled acetyl-CoA fraction is essential for accurate determination of histone acetylation dynamics. Furthermore, we show that without correction, changes in metabolic fluxes would be misinterpreted as changes in histone acetylation dynamics, whereas our proteo-metabo-flux approach allows to distinguish between the two processes.

Conclusions: Our proteo-metabo-flux approach expands the repertoire of metabolic flux analysis and cross-omics and represents a valuable approach to study the regulatory interplay between metabolism and epigenetic regulation by histone acetylation.

Keywords: Computational modelling; Epigenetics; Histone modifications; LC-MS; Metabolic flux analysis; Metabolism.