Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors

Cell Stem Cell. 2009 Oct 2;5(4):420-33. doi: 10.1016/j.stem.2009.07.012.

Abstract

To examine transcription factor (TF) network(s), we created mouse ESC lines, in each of which 1 of 50 TFs tagged with a FLAG moiety is inserted into a ubiquitously controllable tetracycline-repressible locus. Of the 50 TFs, Cdx2 provoked the most extensive transcriptome perturbation in ESCs, followed by Esx1, Sox9, Tcf3, Klf4, and Gata3. ChIP-Seq revealed that CDX2 binds to promoters of upregulated target genes. By contrast, genes downregulated by CDX2 did not show CDX2 binding but were enriched with binding sites for POU5F1, SOX2, and NANOG. Genes with binding sites for these core TFs were also downregulated by the induction of at least 15 other TFs, suggesting a common initial step for ESC differentiation mediated by interference with the binding of core TFs to their target genes. These ESC lines provide a fundamental resource to study biological networks in ESCs and mice.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • CDX2 Transcription Factor
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Line
  • Chromatin Immunoprecipitation
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • GATA3 Transcription Factor / physiology
  • Gene Regulatory Networks / genetics
  • Gene Regulatory Networks / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology
  • Immunoprecipitation
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Kruppel-Like Transcription Factors / physiology
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • SOX9 Transcription Factor / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CDX2 Transcription Factor
  • Cdx2 protein, mouse
  • Esx1 protein, mouse
  • GATA3 Transcription Factor
  • GKLF protein
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Proto-Oncogene Proteins
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Tcf3 protein, mouse
  • Transcription Factors