Architectural Proteins and Pluripotency Factors Cooperate to Orchestrate the Transcriptional Response of hESCs to Temperature Stress

Mol Cell. 2018 Sep 20;71(6):940-955.e7. doi: 10.1016/j.molcel.2018.07.012. Epub 2018 Aug 16.


Cells respond to temperature stress via up- and downregulation of hundreds of genes. This process is thought to be regulated by the heat shock factor HSF1, which controls the release of RNAPII from promoter-proximal pausing. Here, we analyze the events taking place in hESCs upstream of RNAPII release. We find that temperature stress results in the activation or decommissioning of thousands of enhancers. This process involves alterations in the occupancy of transcription factors HSF1, AP-1, NANOG, KLF4, and OCT4 accompanied by nucleosome remodeling by BRG1 and changes in H3K27ac. Furthermore, redistribution of RAD21 and CTCF results in the formation and disassembly of interactions mediated by these two proteins. These alterations tether and untether enhancers to their cognate promoters or refashion insulated neighborhoods, thus transforming the landscape of enhancer-promoter interactions. Details of the 3D interactome remodeling process support loop extrusion initiating at random sites as a mechanism for the establishment of CTCF/cohesin loops.

Keywords: AP-1; CTCF; cohesin; enhancer; heat shock; loop extrusion; pluripotency; stem cell; transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Cell Line
  • Chromatin Immunoprecipitation
  • Chromosomal Proteins, Non-Histone
  • Cohesins
  • DNA Helicases / genetics
  • DNA-Binding Proteins
  • Gene Expression Regulation / physiology*
  • Genes, Homeobox
  • Heat-Shock Response / genetics*
  • Hot Temperature
  • Human Embryonic Stem Cells / metabolism
  • Human Embryonic Stem Cells / physiology*
  • Humans
  • Kruppel-Like Factor 4
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / metabolism
  • Pluripotent Stem Cells / physiology
  • Promoter Regions, Genetic
  • Proteins / genetics
  • RNA Polymerase II
  • Repressor Proteins
  • Stress, Physiological / physiology
  • Temperature
  • Transcription Factor AP-1
  • Transcription Factors / genetics


  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • KLF4 protein, human
  • Kruppel-Like Factor 4
  • NIPBL protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • Proteins
  • RAD21 protein, human
  • Repressor Proteins
  • Transcription Factor AP-1
  • Transcription Factors
  • RNA Polymerase II
  • SMARCA4 protein, human
  • DNA Helicases