HSFs drive transcription of distinct genes and enhancers during oxidative stress and heat shock

Abstract

Reprogramming of transcription is critical for the survival under cellular stress. Heat shock has provided an excellent model to investigate nascent transcription in stressed cells, but the molecular mechanisms orchestrating RNA synthesis during other types of stress are unknown. We utilized PRO-seq and ChIP-seq to study how Heat Shock Factors, HSF1 and HSF2, coordinate transcription at genes and enhancers upon oxidative stress and heat shock. We show that pause-release of RNA polymerase II (Pol II) is a universal mechanism regulating gene transcription in stressed cells, while enhancers are activated at the level of Pol II recruitment. Moreover, besides functioning as conventional promoter-binding transcription factors, HSF1 and HSF2 bind to stress-induced enhancers to trigger Pol II pause-release from poised gene promoters. Importantly, HSFs act at distinct genes and enhancers in a stress type-specific manner. HSF1 binds to many chaperone genes upon oxidative and heat stress but activates them only in heat-shocked cells. Under oxidative stress, HSF1 localizes to a unique set of promoters and enhancers to trans-activate oxidative stress-specific genes. Taken together, we show that HSFs function as multi-stress-responsive factors that activate distinct genes and enhancers when encountering changes in temperature and redox state.

CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses

“…Mapped reads were processed from bed files to coverage files, retaining only the 3′ end nucleotide (active sites of transcription) of each read. Density normalized bedgraph files were adjusted by sample-specific normalization factors as described previously (Booth et al, 2018; Himanen et al, 2022).…”

Targeting HSF1 for cancer treatment: mechanisms and inhibitor development

“…Thus, ROS might manifest both ferroptosis meditated cell death as well as survival signals that lead to an equilibration between cell death and survival outcomes. Moreover, HSF2, a homolog of HSF1, functions in cooperation with HSF1 as the heterotrimer that binds to oxidative stress-specific target genes in response to increased ROS-mediated oxidative stress 129 . Given the recent findings that the interaction between HSF1 and HSF2 is essential for cancer gene expression 24 , 129 , an important role of HSF2 in cancer development may become increasingly significant.…”

Second Virtual International Symposium on Cellular and Organismal Stress Responses, September 8–9, 2022

“…The first session of the meeting was focused on Cellular Stress Responses, starting with Lea Sistonen (Åbo Akademi University, Turku, Finland) who summarized the results of their recently published work on the stress-type specific transcriptional programs driven by the Heat Shock Factors 1 and 2 (HSF1 and HSF2) (Himanen et al 2022 ). The Sistonen lab found that in human cells of epithelial origin, HSF2 is strongly suppressed by TGF-β, which results in destabilized cell–cell adhesion contacts and increased cellular motility.…”