Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. Here, to investigate how divergent transcription is reprogrammed upon stress, we measured nascent RNA synthesis at nucleotide-resolution, and profiled histone H4 acetylation in human cells. Our results globally show that the release of promoter-proximal paused RNA polymerase into elongation functions as a critical switch at which a gene’s response to stress is determined. Highly transcribed and highly inducible genes display strong transcriptional directionality and selective assembly of general transcription factors on the core sense promoter. Heat-induced transcription at enhancers, instead, correlates with prior binding of cell-type, sequence-specific transcription factors. Activated Heat Shock Factor 1 (HSF1) binds to transcription-primed promoters and enhancers, and CTCF-occupied, non-transcribed chromatin. These results reveal chromatin architectural features that orient transcription at divergent regulatory elements and prime transcriptional responses genome-wide.

Proteotoxic stress, that is, stress caused by protein misfolding and aggregation, triggers the rapid and global reprogramming of transcription at genes and enhancers. Genome-wide assays that track transcriptionally-engaged RNA polymerase II (Pol II) at nucleotide resolution have provided key insights into the underlying molecular mechanisms that regulate transcriptional responses to stress. In addition, recent kinetic analyses on transcriptional control under heat stress have shown how cells ‘prewire’ and rapidly execute genome-wide changes in transcription while concurrently becoming poised for recovery. The regulation of Pol II at genes and enhancers in response to heat stress is coupled to chromatin modification and compartmentalization, as well as to co-transcriptional RNA processing. These mechanistic features seem to apply broadly to other coordinated genome-regulatory responses.

Heat shock factor 1 (HSF1) is an evolutionarily highly conserved transcription factor that coordinates stress-induced transcription and directs versatile physiological processes in eukaryotes. The central position of HSF1 in cellular homeostasis has been well demonstrated, mainly through its strong effect in transactivating genes that encode heat shock proteins (HSPs). However, recent genome-wide studies have revealed that HSF1 is capable of reprogramming transcription more extensively than previously assumed; it is also involved in a multitude of processes in stressed and non-stressed cells. Consequently, the importance of HSF1 in fundamental physiological events, including metabolism, gametogenesis and aging, has become apparent and its significance in pathologies, such as cancer progression, is now evident. In this Cell Science at a Glance article, we highlight recent advances in the HSF1 field, discuss the organismal control over HSF1, and present the processes that are mediated by HSF1 in the context of cell type, cell-cycle phase, physiological condition and received stimuli.