Genome-wide Analyses of Transcription Factor GATA3-Mediated Gene Regulation in Distinct T Cell Types

Abstract

Summary The transcription factor GATA3 plays an essential role during T cell development and T helper 2 (Th2) cell differentiation. To understand GATA3-mediated gene regulation, we identified genome-wide GATA3 binding sites in ten well-defined developmental and effector T lymphocyte lineages. In the thymus, GATA3 directly regulated many critical factors, including Th-POK, Notch1 and T cell receptor subunits. In the periphery, GATA3 induced a large number of Th2 cell-specific as well as Th2 cell non-specific genes, including several transcription factors. Our data also indicate that GATA3 regulates both active and repressive histone modifications of many target genes at their regulatory elements near GATA3 binding sites. Overall, although GATA3 binding exhibited both shared and cell-specific patterns among various T cell lineages, many genes were either positively or negatively regulated by GATA3 in a cell type-specific manner, suggesting that GATA3-mediated gene regulation depends strongly on co-factors existing in different T cells.

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

“…We therefore tested whether Gata3 also binds to the TE by chromatin immunoprecipitation (ChIP) assay. Consistent with recent ChIP-Seq results (12), Gata3 also bound to the TE (Fig. 2B), suggesting that Gata3 may activate the Thpok gene through regulating both the TE and PE activity.…”

Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

“…Recent genome-wide analyses suggest that Gata3 mediates both activating and repressive gene regulation (4,5). We therefore reasoned that Gata3 might interact with different cofactors to perform appropriate regulatory functions.…”

“…Among the six vertebrate homologs, Gata1-3 play key roles in the development and maintenance of hematopoietic and immune cells (2). Gata3 plays a critical role in T-cell development in the thymus; it has roles in the CD4 vs. CD8 lineage choice and at the β-selection checkpoint (3), as well as in T helper 2 (Th2) cell differentiation through the activation and repression of transcription (4,5). After antigenic stimulation in a particular cytokine milieu, naïve CD4 T cells differentiate into one of several Th cell subsets including Th1 and Th2 cells (6).…”

“…Conversely, the overexpression of Gata3 in Th1 cells switches their polarity to a Th2 phenotype (11). Recent genome-wide analyses using chromatin immunoprecipitation and microarray analysis (ChIP-chip), ChIP sequence, and RNA sequence (4,5,12) have indicated that Gata3 can directly or indirectly control a large number of Th2 cell-specific genes, as well as other genes including transcription factors such as T-bet (encoded by Tbx21), a key regulator of Th1 cell fate determination (13). Despite its fundamental importance, little is known regarding how the Gata3 transcriptional complex positively and negatively regulates T-cell lineage gene profiles in a cell type-specific manner.…”

“…Several lines of evidence identify Gata3 as a regulator of histone modifications, including histone H3-K9 acetylation (H3-K9Ac); H3-K4me1, 2, and 3; and H3-K27me3 (4,5,15). Such modifications influence transcription by modulating interactions of transcription factors with chromatin (16).…”