Mammalian Heat Shock Response and Mechanisms Underlying Its Genome-wide Transcriptional Regulation

• Published in: Molecular cell 2016-04, Vol.62 (1), p.63-78
• Main Authors: Mahat, Dig B., Salamanca, H. Hans, Duarte, Fabiana M., Danko, Charles G., Lis, John T.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; DNA-Binding Proteins - genetics; Fibroblasts - cytology; Gene Expression Regulation; Heat Shock Transcription Factors; Heat-Shock Proteins - genetics; Heat-Shock Response; Mammals - genetics; Mammals - metabolism; Mice; Promoter Regions, Genetic; RNA Polymerase II - metabolism; Serum Response Factor - genetics; Transcription Factors - genetics; Transcription, Genetic
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.02.025

The heat shock response (HSR) is critical for survival of all organisms. However, its scope, extent, and the molecular mechanism of regulation are poorly understood. Here we show that the genome-wide transcriptional response to heat shock in mammals is rapid and dynamic and results in induction of several hundred and repression of several thousand genes. Heat shock factor 1 (HSF1), the “master regulator” of the HSR, controls only a fraction of heat shock-induced genes and does so by increasing RNA polymerase II release from promoter-proximal pause. Notably, HSF2 does not compensate for the lack of HSF1. However, serum response factor appears to transiently induce cytoskeletal genes independently of HSF1. The pervasive repression of transcription is predominantly HSF1-independent and is mediated through reduction of RNA polymerase II pause release. Overall, mammalian cells orchestrate rapid, dynamic, and extensive changes in transcription upon heat shock that are largely modulated at pause release, and HSF1 plays a limited and specialized role. [Display omitted] •∼1,500 genes are up- and ∼8,000 are downregulated during the first hour of heat shock•HSF1 induces heat shock protein genes by increasing promoter-proximal pause release•Upon heat shock, SRF transiently induces immediate-early cytoskeletal genes•Broad repression during heat shock in mammals occurs by inhibiting pause release Using PRO-seq, Mahat et al. identify hundreds of genes that are upregulated and thousands that are downregulated transcriptionally in mammals during heat shock. A majority of this regulation is independent of HSF1 and HSF2, and many rapidly and transiently upregulated cytoskeletal genes depend on SRF. Both upregulation and downregulation are modulated at promoter-proximal pause release.