Acetyl-CoA production by Mediator-bound 2-ketoacid dehydrogenases boosts de novo histone acetylation and is regulated by nitric oxide.

Veronica Vallelonga, Gioacchino Natoli, Fabio Bedin, Chiara Ghirardi, Mattia Marenda, Pierluigi Di Chiaro, Carolina Borriero, Francesco Gualdrini, Marta Russo, Serena Ghisletti, Silvia Pedretti, Gabriele Imperato, Alessandro Cuomo, Tiziana Bonaldi, Roberta Noberini, Simona Rodighiero, Sara Polletti, Nico Mitro, Elena Prosperini

Journal: Molecular cell 2024;84(5):967-980.e10

PMID: 38242130

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Abstract

Histone-modifying enzymes depend on the availability of cofactors, with acetyl-coenzyme A (CoA) being required for histone acetyltransferase (HAT) activity. The discovery that mitochondrial acyl-CoA-producing enzymes translocate to the nucleus suggests that high concentrations of locally synthesized metabolites may impact acylation of histones and other nuclear substrates, thereby controlling gene expression. Here, we show that 2-ketoacid dehydrogenases are stably associated with the Mediator complex, thus providing a local supply of acetyl-CoA and increasing the generation of hyper-acetylated histone tails. Nitric oxide (NO), which is produced in large amounts in lipopolysaccharide-stimulated macrophages, inhibited the activity of Mediator-associated 2-ketoacid dehydrogenases. Elevation of NO levels and the disruption of Mediator complex integrity both affected de novo histone acetylation within a shared set of genomic regions. Our findings indicate that the local supply of acetyl-CoA generated by 2-ketoacid dehydrogenases bound to Mediator is required to maximize acetylation of histone tails at sites of elevated HAT activity.

Address: Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy. Electronic address: [email protected].; Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy. Electronic address: [email protected].; Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy.; DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano 20133, Italy.; Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy; Department of Hematology and Hematology-Oncology (DIPO), Università degli Studi di Milano, Milano 20122, Italy.; Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy; DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano 20133, Italy.; Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy. Electronic address: [email protected].; Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan 20139, Italy. Electronic address: [email protected].

DOI: 10.1016/j.molcel.2023.12.033

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MeSH Terms: Histones, Acetyl Coenzyme A, Acetylation, Nitric Oxide, Mediator Complex, Oxidoreductases