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Deletion of the transcription factors Hsf1, Msn2 and Msn4 in yeast uncovers transcriptional reprogramming in response to proteotoxic stress

ABSTRACT: The heat shock response is an ancient and ubiquitous program allowing organisms to survive adverse environmental conditions. In S. cerevisiae, three transcription factors, Hsf1, Msn2 and Msn4, are thought to regulate the stress response. While Msn2/4 can be deleted, Hsf1 is essential. By combining the depletion of Hsf1 with the deletion of Msn2 and Msn4, we were able to switch off the central stress response. We show that the transcription factors Hsf1 and Msn2/4 follow different strategies and regimes: Whereas Msn2/4 are responsible for a broad metabolic response, Hsf1 triggers a direct chaperone response to stabilize and repair unfolded proteins. Exposure of cells lacking Msn2/4 and Hsf1 to thermal stress resulted in massive protein aggregation. Comparison with wildtype yeast revealed that among the proteins rescued by the stress response are many essential proteins.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Moritz Mühlhofer

LAB HEAD: Johannes Buchner

PROVIDER: PXD024352 | Pride | 2024-01-31

REPOSITORIES: Pride

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Project description:Heat shock response (HSR) is critical for survival of organisms undergoing proteotoxic stress. Heat shock factor 1 (HSF1) is widely believed to be the master regulator of this response. Here, we examined the kinetics of the transcriptional response and HSF1 binding changes genome-wide after heat shock (HS) with high sensitivity and high spatial and temporal resolution using PRO-seq and ChIP-seq assays respectively in wild type and in hsf1-deletion mouse embryonic fibroblasts. The transcriptional response is rapid, dynamic, and extensive with activation of several hundred genes and repression of several thousands of genes. Although HSF1 is critically required for classical inducible Heat Shock Protein (HSP) genes, it is not required for the majority of gene activation. HSF1 acts mechanistically to promote RNA polymerase II (Pol II) release from the promoter-proximal pause, while recruitment and initiation of Pol II are predominantly HSF1-independent. Surprisingly, a major class of cytoskeleton genes is immediately (within 2.5 minutes) and transiently activated in an HSF1-independent manner. A second wave of regulation is characterized by robust activation or repression of new sets of genes. The broad repression of thousands of genes, a quarter of which are repressed immediately upon HS and the rest are repressed in the second wave of regulation, is mediated at the level of decreasing Pol II pause release and not at prior steps of Pol II recruitment or initiation. Notably, heat shock does not induce transcription of some previously defined HSP genes, and HSF2 â a homolog of HSF1 â does not compensate for the lack of HSF1. Together, these findings indicate that mammalian cells cope with stress by rapidly inducing pervasive and dramatic changes in transcription that are largely modulated at the step of pause release, and only a fraction of this regulation is HSF1-dependent. Examination of transcriptional regulation before and after heat shock in WT, HSF1-/-, and HSF1&2-/- MEFs

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Deletion of the transcription factors Hsf1, Msn2 and Msn4 in yeast uncovers transcriptional reprogramming in response to proteotoxic stress

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