Gene

Cell biology

Linguistics

Philosophy

Biology

Heat shock protein

Heat shock

Transcription (linguistics)

Hsp70

Genetics

HSF1

Transcription factor

Chemistry

HSPA4

Heat shock factor

Nature Cell Biology

Heat-shock transcription factor 1 (HSF1) orchestrates the fast and vast cellular response to heat shock through increased expression of heat-shock proteins. However, how HSF1 rapidly and reversibly regulates transcriptional reprogramming remains poorly defined. Here by combining super-resolution imaging, in vitro reconstitution and high-throughput sequencing, we reveal that HSF1 forms small nuclear condensates via liquid–liquid phase separation at heat-shock-protein gene loci and enriches multiple transcription apparatuses through co-phase separation to promote the transcription of target genes. Furthermore, the phase-separation capability of HSF1 is fine-tuned through phosphorylation at specific sites within the regulatory domain. Last, we discovered that HSP70 disperses HSF1 condensates to attenuate transcription following the cessation of heat shock and further prevents the gel-like phase transition of HSF1 under extended heat-shock stress. Our work reveals an inducible and reversible phase-separation feedback mechanism for dynamic regulation of HSF1 activity to drive the transcriptional response and maintain protein homeostasis during acute stress. Zhang, Shao and coworkers report that HSF1 forms small condensates at its target gene loci to promote their transcription during acute heat stress. The produced HSP70 proteins in turn disperse HSF1 condensates to shut off the heat-shock response.

Reversible phase separation of HSF1 is required for an acute transcriptional response during heat shock