FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity

Cell Stem Cell. 2016 Jan 7;18(1):104-17. doi: 10.1016/j.stem.2015.10.003.


Early development is governed by the ability of pluripotent cells to retain the full range of developmental potential and respond accurately to developmental cues. This property is achieved in large part by the temporal and contextual regulation of gene expression by enhancers. Here, we evaluated regulation of enhancer activity during differentiation of embryonic stem to epiblast cells and uncovered the forkhead transcription factor FOXD3 as a major regulator of the developmental potential of both pluripotent states. FOXD3 bound to distinct sites in the two cell types priming enhancers through a dual-functional mechanism. It recruited the SWI/SNF chromatin remodeling complex ATPase BRG1 to promote nucleosome removal while concurrently inhibiting maximal activation of the same enhancers by recruiting histone deacetylases1/2. Thus, FOXD3 prepares cognate genes for future maximal expression by establishing and simultaneously repressing enhancer activity. Through switching of target sites, FOXD3 modulates the developmental potential of pluripotent cells as they differentiate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Cell Lineage
  • DNA Helicases / metabolism*
  • Enhancer Elements, Genetic*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / metabolism*
  • Nucleosomes / metabolism
  • Pluripotent Stem Cells / cytology*
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Transcription Factors / metabolism*


  • Forkhead Transcription Factors
  • Foxd3 protein, mouse
  • Histones
  • Nuclear Proteins
  • Nucleosomes
  • Repressor Proteins
  • Transcription Factors
  • Histone Deacetylases
  • Smarca4 protein, mouse
  • DNA Helicases