Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Am J Physiol Regul Integr Comp Physiol. 2014 Sep 15;307(6):R608-20. doi: 10.1152/ajpregu.00085.2014. Epub 2014 Jun 18.


Inducible gene expression, which requires chromatin remodeling on gene promoters, underlies the epigenetically inherited differentiation program of most immune cells. However, chromatin-mediated mechanisms that underlie these events in T regulatory cells remain to be fully characterized. Here, we report that inducibility of FOXP3, a key transcription factor for the development of T regulatory cells, depends upon Kruppel-like factor 10 (KLF10) interacting with two antagonistic histone-modifying systems. We utilized chromatin immunoprecipitation, genome-integrated reporter assays, and functional domain KLF10 mutant proteins, to characterize reciprocal interactions between this transcription factor and either the Sin3-histone deacetylase complex or the histone acetyltransferase, p300/CBP-associated factor (PCAF). We characterize a Sin3-interacting repressor domain on the NH2 terminus of KLF10, which works to limit the activating function of this transcription factor. Indeed, inactivation of this Sin3-interacting domain renders KLF10 able to physically associate with PCAF as to induce FOXP3 gene transcription. We show that this biochemical data derived from studying our genome-integrated reporter cell system are recapitulated in primary murine lymphocytes. Collectively, these results advance our understanding of how a single transcription factor, namely KLF10, functions as a toggle to integrate antagonistic signals regulating FOXP3 and, thus, immune activation.

Keywords: FOXP3; KLF10; PCAF; Sin3; T regulatory cell.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Chromatin Assembly and Disassembly
  • Colitis / chemically induced
  • Colitis / enzymology*
  • Colitis / genetics
  • Colitis / immunology
  • Colon / enzymology*
  • Colon / immunology
  • Dextran Sulfate
  • Disease Models, Animal
  • Early Growth Response Transcription Factors / chemistry
  • Early Growth Response Transcription Factors / deficiency
  • Early Growth Response Transcription Factors / genetics
  • Early Growth Response Transcription Factors / metabolism*
  • Epigenesis, Genetic
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Jurkat Cells
  • Kruppel-Like Transcription Factors / chemistry
  • Kruppel-Like Transcription Factors / deficiency
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Mutation
  • Promoter Regions, Genetic
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Signal Transduction
  • Sin3 Histone Deacetylase and Corepressor Complex / chemistry
  • Sin3 Histone Deacetylase and Corepressor Complex / metabolism*
  • T-Lymphocytes, Regulatory / enzymology*
  • T-Lymphocytes, Regulatory / immunology
  • Transfection
  • Up-Regulation
  • p300-CBP Transcription Factors / metabolism*


  • Early Growth Response Transcription Factors
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • KLF10 protein, human
  • KLF10 protein, mouse
  • Kruppel-Like Transcription Factors
  • Dextran Sulfate
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sin3 Histone Deacetylase and Corepressor Complex