title: T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements.
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.
authors.affiliation: Division of Infection and Immunity and UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Aditi
authors.initials: A
authors.lastname: Kanhere
authors.forename: Arnulf
authors.initials: A
authors.lastname: Hertweck
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bhatia
authors.forename: M Refik
authors.initials: MR
authors.lastname: Gökmen
authors.forename: Esperanza
authors.initials: E
authors.lastname: Perucha
authors.forename: Ian
authors.initials: I
authors.lastname: Jackson
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.forename: Richard G
authors.initials: RG
authors.lastname: Jenner
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D050990:GATA3 Transcription Factor / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D012045:Regulatory Sequences, Nucleic Acid; D020825:T-Box Domain Proteins / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D000098815:T-bet Transcription Factor
chemical_list: D050990:GATA3 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor