Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells

Cell Rep. 2013 Dec 26;5(6):1611-24. doi: 10.1016/j.celrep.2013.11.021. Epub 2013 Dec 12.

Abstract

A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the transforming growth factor β (TGF-β) pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex composed of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGF-β pathway (SMAD2/3), and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements, and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch-enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Developmental
  • Germ Layers / cytology
  • Germ Layers / metabolism
  • Humans
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • FOXH1 protein, human
  • Forkhead Transcription Factors
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TAZ protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE52440