Transcriptional memory dampens heat shock responses in yeast: functional role of Mip6 and its interaction with Rpd3

Cells must rapidly adapt to environmental fluctuations, including heat stress, to maintain homeostasis and ensure survival. A key adaptive mechanism is transcriptional memory, which enables cells to "remember" prior stress exposure and mount a faster or more controlled transcriptional response upon reexposure. However, the molecular mechanisms underlying transcriptional memory in the heat shock response (HSR) remain incompletely understood. Here, we investigate the role of the RNA-binding protein (RBP) Mip6 in regulating transcriptional memory during heat stress in Saccharomyces cerevisiae. Using qRT-PCR and RNA-seq, we demonstrate that prior heat shock exposure dampens the activation of heat-responsive genes upon a second stress, a phenomenon more pronounced in mip6Δ mutants. Our transcriptomic analyses reveal that transcriptional memory predominantly suppresses excessive gene expression changes, fine-tuning stress responses. Moreover, we identify a functional and physical interaction between Mip6 and the histone deacetylase Rpd3, a key regulator of transcriptional memory. Loss of both Mip6 and Rpd3 results in synthetic growth defects under heat stress and misregulation of Msn2/4-dependent transcripts, implicating Mip6 as a novel player in the coordination of chromatin and RNA-binding mechanisms during transcriptional memory. Additionally, we show that transcriptional memory modulates metabolic homeostasis and proteostasis. Collectively, our findings implicate Mip6 in the coordination of transcriptional memory in the HSR and reveal a novel link between the RBP Mip6 and the chromatin modifier Rpd3 HDAC in stress adaptation. These insights provide a foundation for further exploration of transcriptional memory mechanisms across diverse stress conditions.