The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding

PLoS Genet. 2015 Jun 24;11(6):e1005251. doi: 10.1371/journal.pgen.1005251. eCollection 2015 Jun.


The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3's function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation. Our study suggests that Foxp3, even in the absence of its DNA-binding forkhead domain, acts as a bridge between DNA-binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We show that, in one such mechanism, Foxp3 recruits class I histone deacetylases to the promoters of target genes, counteracting activation-induced histone acetylation and thereby suppressing their expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Nucleus / metabolism
  • DNA / metabolism*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / physiology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Histones
  • Interleukin-2
  • DNA
  • Histone Deacetylases