STRESS-SPECIFIC GENOME-WIDE PROGRAMS OF GENES AND ENHANCERS
Cells are exposed to various types of cytotoxic stress including oxidative stress, elevated temperatures and toxins. Surviving stressful conditions requires extensive reprogramming of transcription, which involves both upregulation and downregulation of genes. Heat shock has provided an excellent model to investigate how nascent transcription is regulated in cells exposed to proteotoxic stress. However, knowledge of transcriptional regulation during other types of stress is lacking. In this comprehensive study, the transcriptional reprogramming of genes and enhancers was analyzed upon two different types of stress, i.e. oxidative stress and heat shock by combining two different genome-wide analyses (PRO-seq and ChIP-seq). This approach allowed determining the target repertoire of both genes and enhancers that are regulated by two important stress-inducible transcription factors, HSF1 and HSF2.
This study revealed several exciting and surprising findings. HSF1 and HSF2 drive stress type-specific transcription programs, as their target genes in the oxidative stress response are different from the classical chaperone genes in the heat shock response. Moreover, besides functioning as promoter-binding transcription factors, both HSFs activate genes through enhancers in response to oxidative stress and heat shock. Intriguingly, in contrast to promoter-bound HSF1, which regulates classical chaperone genes, recruitment of HSF1 to enhancers is required for the induction of genes encoding proteins that reside in the plasma membrane. Taken together, this study highlights the unique property of HSFs being able to drive distinct transcription programs, through gene promoters and enhancers, depending on the type of stress. It is plausible that the capacity of HSFs to orchestrate transcription via enhancers is not limited to stress, since HSFs play important roles also in developmental and pathological processes, such as progression of cancer.
Himanen S.V., Puustinen M.C., Da Silva A.J., Vihervaara A. & Sistonen L. HSFs drive transcription of distinct genes and enhancers during oxidative stress and heat shock. Nucleic Acids Research 2022 June 10. DOI: 10.1093/nar/gkac493. Online ahead of print.