Bcl11b, a novel GATA3-interacting protein, regulates T-helper-2-cell differentiation and function

Abstract

Abstract GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. Fine-tuning GATA3 transcription activity is critical for effectively expelling extracellular parasites and preventing allergic disorders. However, it is still elusive how GATA3 function is regulated in Th2 cells. Here, we report that the transcription factor B-cell Lymphoma 11b (Bcl11b) is a novel component of the GATA3 transcriptional complex executing GATA3-mediated gene expression. Bcl11b binds to GATA3 through protein-protein interaction; ChIP-Seq analysis showed co-localization of Bcl11b and GATA3 at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent indicating that Bcl11b inhibits GATA3-mediated cytokines production. Genome-wide analysis of Bcl11b- and GATA3-mediated gene regulation (RNA-Seq) and co-binding pattern (ChIP-Seq) suggests that GATA3/Bcl11b complex are involved in limiting Th2 gene expression as well as inhibiting non-Th2 gene expression. Thus, Bcl11b, a previously unknown GATA3 binding protein, fine-tunes GATA3-mediated gene expression in Th2 cells.