The authors first induced glucose starvation in Saccharomyces cerevisiae cells in exponential growth phase, and confirmed that this depleted the cells of intracellular acetyl-CoA. This resulted in global loss of acetylation of multiple lysines on the tail of histone H3, but not on that of H4. ChIP-seq studies of the most glucose-responsive mark, H3K9ac, determined that most genes had lower levels of H3K9ac in glucose-starvation conditions, consistent with global loss of acetylation. However, the genomic landscape of H3K9ac was not altered in a uniform way. Although H3K9ac can be found to locate rather evenly at the transcription start sites of many genes in normal conditions, after starvation, H3K9ac is refocused on genes encoding molecules involved in carbon metabolism, which is accompanied by increased transcription of these genes. Overall, the authors observed glucose starvation–induced changes to histone H3K9ac and transcription of genes encoding molecules involved in gluconeogenesis and fat metabolism, two metabolic pathways that cells activate to utilize alternative sources of carbon.
The authors next investigated the dynamics and regulation of histone modification in response to carbon starvation. They first assessed the role of the histone acetyltransferase Gcn5p, which acetylates lysines on H3. Whereas loss of Gcn5p in normal growth conditions resulted in a drop in global H3K9ac in cells, there were only relatively mild effects on gene expression. However, loss of Gcn5p in carbon-deprived cells resulted in both a loss of histone-acetylation re-focusing and reduced gene expression, particularly of genes required for gluconeogenesis and fat metabolism. Gcn5p is the histone acetyltransferase catalytic subunit of the SAGA transcriptional coactivator complex, and the authors next confirmed that gluconeogenic and fat-metabolism genes in carbon-starved cells showed enrichment for SAGA, concomitant with enrichment for H3K9ac. In starvation conditions, SAGA also seemed to associate with starvation-specific transcription factors at the target genes. With glucose starvation resulting in a net loss of acetylation in cells, the authors finally confirmed that histone deacetylation is required for the H3K9ac-dependent transcriptional changes, finding that the histone deacetylase Rpd3p, the main histone deacetylase for H3 in yeast, was required for the starvation-induced switch in histone acetylation and gene expression.
This is a preview of subscription content, access via your institution