Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells

Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3388-97. doi: 10.1073/pnas.1305275110. Epub 2013 Aug 19.

Abstract

Heat shock factors (HSFs) are the master regulators of transcription under protein-damaging conditions, acting in an environment where the overall transcription is silenced. We determined the genomewide transcriptional program that is rapidly provoked by HSF1 and HSF2 under acute stress in human cells. Our results revealed the molecular mechanisms that maintain cellular homeostasis, including HSF1-driven induction of polyubiquitin genes, as well as HSF1- and HSF2-mediated expression patterns of cochaperones, transcriptional regulators, and signaling molecules. We characterized the genomewide transcriptional response to stress also in mitotic cells where the chromatin is tightly compacted. We found a radically limited binding and transactivating capacity of HSF1, leaving mitotic cells highly susceptible to proteotoxicity. In contrast, HSF2 occupied hundreds of loci in the mitotic cells and localized to the condensed chromatin also in meiosis. These results highlight the importance of the cell cycle phase in transcriptional responses and identify the specific mechanisms for HSF1 and HSF2 in transcriptional orchestration. Moreover, we propose that HSF2 is an epigenetic regulator directing transcription throughout cell cycle progression.

Keywords: ChIP-seq; ENCODE; human genome; proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / genetics
  • Blotting, Western
  • Cell Cycle / genetics*
  • Chromatin / genetics*
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Response / genetics*
  • Humans
  • K562 Cells
  • Male
  • Mitosis / genetics*
  • Molecular Chaperones / genetics
  • Polyubiquitin / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptional Activation

Substances

  • Chromatin
  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Transcription Factors
  • Polyubiquitin
  • HSF2 protein, human

Associated data

  • GEO/GSE43579