T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements

Nat Commun. 2012;3:1268. doi: 10.1038/ncomms2260.

Abstract

T-bet and GATA3 regulate the CD4+ T cell Th1/Th2 cell fate decision but little is known about the interplay between these factors outside of the murine Ifng and Il4/Il5/Il13 loci. Here we show that T-bet and GATA3 bind to multiple distal sites at immune regulatory genes in human effector T cells. These sites display markers of functional elements, act as enhancers in reporter assays and are associated with a requirement for T-bet and GATA3. Furthermore, we demonstrate that both factors bind distal sites at Tbx21 and that T-bet directly activates its own expression. We also show that in Th1 cells, GATA3 is distributed away from Th2 genes, instead occupying T-bet binding sites at Th1 genes, and that T-bet is sufficient to induce GATA3 binding at these sites. We propose these aspects of T-bet and GATA3 function are important for Th1/Th2 differentiation and for understanding transcription factor interactions in other T cell lineage decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / physiology
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Differentiation / physiology
  • GATA3 Transcription Factor / physiology*
  • Gene Expression Regulation, Developmental / physiology
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Oligonucleotide Array Sequence Analysis
  • Regulatory Sequences, Nucleic Acid
  • T-Box Domain Proteins / physiology*
  • Th1 Cells / physiology*
  • Th2 Cells / physiology*

Substances

  • GATA3 Transcription Factor
  • T-Box Domain Proteins
  • T-box transcription factor TBX21

Associated data

  • GEO/GSE31320