MassIVE MSV000099224

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Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation

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Description

Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. In this work, we focused on deciphering metabolic pathways in the nucleus that control acetylation of histone proteins and identified a novel mechanism that directs local abundance of acetyl-CoA pool by nuclear localization of mitochondrial enzymes, aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies identified reductive carboxylation of alpha-ketoglutarate catalyzed by IDH2 and ACO2 rapidly synthesize citrate to increase the acetyl-CoA pool in the nucleus. Genetic and proteomic analyses revealed nuclear IDH2 and ACO2, form a complex with KAT2A for histone acetylation, which increased chromatin accessibility and recruited pioneering transcription factors such as FOXA1 to activate proliferative genes. In multiple mouse models of cancer, increased nuclear expression of ACO2 and IDH2 was sufficient to develop aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work revealed a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors. The files deposited here correspond to the analysis of heavy acetyl groups (13C2) on histones after incubation of MDA-MB-468 cells with 4 mM U-13C-glutamine for 2 hours. The cells were engineered to stably express shRNA against ACO2, with or without expression of a nuclear-localized ACO2 (ACO2-dMTS-NLS), or a non-targeting control shRNA. Histones were derivatized with propionic anhydride and digested with trypsin prior to LC-MS/MS analysis with a DIA method. [doi:10.25345/C5BR8MV6S] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Histone acetylation ; TCA cycle ; Epigenetics ; DatasetType:Proteomics

Contact

Principal Investigators:
(in alphabetical order) 		Peder Lund, University of Pennsylvania, United States
Submitting User: pederl

Publications

Sawant Dessai A, Elhalawany NA, Dai T, Jacobi JJ, Prechtl C, Dimeck AN, Morton SR, Long MD, Singh PK, Putluri N, Lopes M, Liu S, Smiraglia DJ, Gurova KV, Lund PJ, Gates LA, Jung SY, Dasgupta S.
Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
Nat Commun. Epub 2026 Jul 1.

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