Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce FOXA1-dependent gene activation [C42_ATAC]

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 moonlighting mechanism that directs local abundance of acetyl-CoA pool by nuclear localization of mitochondrial enzymes, aconitase (ACO2), and isocitrate dehydrogenase (IDH2). Metabolic tracing studies in the isolated nucleus identified reductive carboxylation of α-ketoglutarate catalyzed by IDH2 and ACO2 rapidly synthesize citrate to increase the acetyl-CoA pool. Genetic and proteomic analyses revealed nuclear IDH2 and ACO2, form a complex with KAT2A for histone acetylation, which increased chromatin accessibility and recruited pioneering factor FOXA1 to activate proliferative gene MKI67. 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.