Yeast Rpd3L histone deacetylase couples nutrient shifts to genome-wide chromatin reprogramming.

Adaptive transcriptional rewiring underlies the metabolic flexibility of Saccharomyces cerevisiae. We demonstrate that the histone deacetylase Rpd3 mediates nutrient-dependent chromatin reprogramming that coordinates transcriptional shutdown and global acetylation balance during metabolic transitions. Genome-wide analyses reveal that Rpd3 complexes drive rapid, reversible histone deacetylation across promoters and gene bodies, fine-tuning transcriptional output. Rpd3, primarily through the large complex (Rpd3L), localizes at promoters of active genes enriched in H3K9ac and the acetyltransferase Gcn5. Upon nutrient shift, Gcn5 disengages while Rpd3-mediated H3K9 deacetylation enforces repression. Loss of Rpd3 or its Rpd3L-specific subunit, Pho23, disrupts this balance, resulting in the aberrant persistence of growth programs upon starvation and defective activation of respiratory genes in the presence of glucose. HDACs thus can act as metabolic gatekeepers, coupling nutrient cues to chromatin reprogramming and ensuring transcriptional fidelity during metabolic transitions, thereby resolving the long-standing paradox of HDAC enrichment at active promoters.