GATA-binding protein 3 (Gata3) controls the differentiation of naive CD4 T cells into T helper 2 (Th2) cells by induction of chromatin remodeling of the Th2 cytokine gene loci, direct transactivation of Il5 and Il13 genes, and inhibition of Ifng. Gata3 also facilitates Th2 cell proliferation via additional mechanisms that are far less well understood. We herein found that Gata3 associates with RuvB-like protein 2 (Ruvbl2) and represses the expression of a CDK inhibitor, cyclin-dependent kinase inhibitor 2c (Cdkn2c) to facilitate the proliferation of Th2 cells. Gata3 directly bound to the Cdkn2c locus in an Ruvbl2-dependent manner. The defect in the proliferation of Gata3-deficient Th2 cells is rescued by the knockdown of Cdkn2c, indicating that Cdkn2c is a key molecule involved in the Gata3-mediated induction of Th2 cell proliferation. Ruvbl2-knockdown Th2 cells showed decreased antigen-induced expansion and caused less airway inflammation in vivo. We therefore have identified a functional Gata3/Ruvbl2 complex that regulates the proliferation of differentiating Th2 cells through the repression of a CDK inhibitor, Cdkn2c.

GATA binding protein 3 (Gata3) is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4-nucleosome remodeling histone deacetylase repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.

The analysis of Fgf10 mouse mutants has demonstrated a critical role for this ligand in neurosensory development of the vertebrate inner ear, and we have been looking to define the direct upstream regulators of Fgf10 in this sensory organ, as part of constructing the programme of early inner ear development. Through the analysis of reporter constructs in transgenic mouse embryos and neonatal mice, in this report we define a minimal 1400 bp enhancer from the 5' flanking region of Fgf10. This enhancer drives reporter transgene expression in a manner that recapitulates endogenous expression of Fgf10, from its initial onset in the invaginating otic placode and onwards throughout gestation, controlling Fgf10 expression in all developing sensory patches and in the developing VIIIth ganglion. This regulatory region includes three putative Gata3 binding sites that we demonstrate directly interacts with Gata3 protein through the DNA binding domain with differing affinities. Site directed mutagenesis of all three sites and functional testing in transgenic embryos using reporter transgenes reveals an absolute requirement for Gata3 in controlling Fgf10 expression. Transgenic analysis of individual Gata3 binding site mutations illustrates that only one of these binding sites is necessary for reporter expression. Together these data demonstrate that Gata3 directly activates Fgf10 in the early inner ear, and does so through a single binding site.
Copyright © 2012 Elsevier Inc. All rights reserved.

Sox4 is a transcription factor that regulates various developmental processes. Here we show that Sox4 was induced by TGF-β and negatively regulated the transcription factor GATA-3, the master regulator of function of T helper type 2 (T(H)2) cells, by two distinct mechanisms. First, Sox4 bound directly to GATA-3, preventing its binding to GATA-3 consensus DNA sequences. Second, Sox4 bound to the promoter region of the gene encoding interleukin 5 (IL-5), a T(H)2 cytokine, and prevented binding of GATA-3 to this promoter. T(H)2 cell-driven airway inflammation was modulated by alterations in Sox4 expression. Thus, Sox4 acted as a downstream target of TGF-β to inhibit GATA-3 function, T(H)2 differentiation and T(H)2 cell-mediated inflammation.