BioProject

The goal of the study was to understand whether mitochondrial-driven epigenetic changes regulate gene expression. More...

The goal of the study was to understand whether mitochondrial-driven epigenetic changes regulate gene expression. Mitochondrial metabolism has been implicated in epigenetics but the extent to which this impacts gene expression is unclear. Here we show that loss of mitochondrial DNA (mtDNA) results in locus-specific alterations in histone acetylation, DNA methylation and expression of a subset of genes. Most of these changes are rescued by restoring mitochondrial electron transport in a way that maintains the oxidative tricarboxylic acid cycle, but not reactive oxygen species or ATP production, or by modulating the mitochondrial pool of acetyl-CoA. Changes in acetyl-CoA and histone acetylation precede overt mitochondrial dysfunction and significant changes in gene expression and DNA methylation. This suggests that acetyl-CoA levels signal mitochondrial status to the nucleus. Differentially expressed genes with altered histone marks or DNA methylation regulate amino acid degradation, which likely compensates for the changes in acetyl-CoA and one carbon metabolism. These have the potential to further affect methylation reactions, redox control and nucleotide levels. These results illustrate the extent to which mitochondria impact cell physiology through epigenetic remodeling. Overall design: ChIP-seq for H3K9ac and 27ac marks was performed in rho0 cells, which are chronically depleted of mtDNA, prior to and after supplemention of the cell culture media for 4h with the cell permeable metabolite DM-α-KG. This exposure increases both the total levels of acetyl-CoA, of histone acetyltransferase activity and of histone acetylation in these cells. Less...