Dataset Information

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

ABSTRACT: Histone modifying enzymes depend on the availability of cofactors, with acetyl-CoA being required for lysine acetyltransferase (KAT) activity. The discovery that mitochondrial acyl-CoA producing enzymes are also delivered to the nucleus, suggests that high concentrations of metabolites generated locally may impact acetylation of histones and other nuclear substrates and eventually control gene regulation. Here we show that 2-ketoacid dehydrogenase complexes were stably associated with the Mediator complex in macrophages, 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 LPS-stimulated macrophages, inhibited both the activity of 2-ketoacid dehydrogenases and their association with Mediator. Consequently, NO reduced de novo histone acetylation at genomic regions with high acetyl-CoA deposition rates. Our findings indicate that a local supply of acetyl-CoA generated by Mediator-bound 2-ketoacid dehydrogenases is required to maximize acetylation of histone tails at sites of elevated HAT activity.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow

SUBMITTER: Roberta Noberini

LAB HEAD: Tiziana Bonaldi

PROVIDER: PXD040937 | Pride | 2024-02-14

REPOSITORIES: Pride

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Publications

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

Russo Marta M Gualdrini Francesco F Vallelonga Veronica V Prosperini Elena E Noberini Roberta R Pedretti Silvia S Borriero Carolina C Di Chiaro Pierluigi P Polletti Sara S Imperato Gabriele G Marenda Mattia M Ghirardi Chiara C Bedin Fabio F Cuomo Alessandro A Rodighiero Simona S Bonaldi Tiziana T Mitro Nico N Ghisletti Serena S Natoli Gioacchino G

Molecular cell 20240118 5

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 co ...[more]

PMID: 38242130

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Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.

Dataset Information

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

Publications

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

Similar Datasets

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