Mitochondrial Metabolic Dysfunction Drives Protein Hyperacylation that Weakens Nucleosomes

Abstract

Though many studies have explored the influence of epigenetics on cellular metabolism, the impact of metabolic changes on chromatin organization is not well understood. This is despite the fact that many metabolites are substrates for epigenetic modifier enzymes known to participate in chromatin reorganization. Various acyl-coenzyme A (CoA) metabolites participate in energy production, including fatty acid oxidation and the citric acid cycle. These metabolites are also acylating agents that transfer acyl groups to proteins, including histones in nucleosomes, altering the charge of lysine residues. We used optical tweezers to study reconstituted nucleosome arrays and demonstrate that spontaneous lysine acylation by various acyl-CoAs in vitro directly destabilizes histone octamer-DNA interactions. We found that acylation preferentially targets histone tails, especially tails of the (H3-H4)2 tetramer, though the (H2A/H2B) dimers are also affected. Acylation destabilizes histone-DNA interactions, leading to the release of the outer ½ turns of wrapped DNA from the entry and exit of the nucleosome. The remaining structure exhibits a measurable increase in the rate of nucleosomal ‘breathing’. Destabilization increases systematically as progressively larger acyl chains are added, beginning with acetyl-CoA and expands with the introduction of negatively charged succinyl groups by incubation with succinyl-CoA. Finally, we reveal that lysine acylation promotes thermally driven octamer sliding. Together, these results elucidate the role that nucleosome acylation may play to facilitate RNA polymerase II transcription.