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

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.