Differential coupling of KLF10 to sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Yuning Xiong, Phyllis A. Svingen, Olga O. Sarmento, Thomas C. Smyrk, Maneesh Dave, Sahil Khanna, Gwen A. Lomberk, Raul A. Urrutia, William A. Faubion

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 acetyl-transferase, 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.

Original languageEnglish (US)
Pages (from-to)R608-R620
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume307
Issue number6
DOIs
StatePublished - Sep 15 2014

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Keywords

  • FOXP3
  • KLF10
  • PCAF
  • Sin3
  • T regulatory cell

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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