Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles

Abstract

Changes in transcription factor levels and activities dictate developmental fate. Such a change might affect the full ensemble of target genes for a factor or only uniquely sensitive targets. We investigated the relationship among activity of the hematopoietic transcription factor GATA-1, chromatin occupancy, and target gene sensitivity. Graded activation of GATA-1 in GATA-1-null cells revealed high-, intermediate-, and low-sensitivity targets. GATA-1 activity requirements for occupancy and transcription often correlated. A GATA-1 amino-terminal deletion mutant severely deregulated the low-sensitivity gene Tac-2. Thus, cells expressing different levels of a cell type-specific activator can have qualitatively distinct target gene expression patterns, and factor mutations preferentially deregulate low-sensitivity genes. Unlike other target genes, GATA-1-mediated Tac-2 regulation was bimodal, with activation followed by repression, and the coregulator Friend of GATA-1 (FOG-1) selectively mediated repression. A GATA-1 mutant defective in FOG-1 binding occupied a Tac-2 regulatory region at levels higher than wild-type GATA-1, whereas FOG-1 facilitated chromatin occupancy at a distinct target site. These results indicate that FOG-1 is a determinant of GATA factor target gene sensitivity by either facilitating or opposing chromatin occupancy.chromatin ͉ erythroid ͉ GATA ͉ hematopoietic

Transcriptional regulation by GATA1 and GATA2 during erythropoiesis

“…In contrast, erythroid genes expressed during the later stages may have a high threshold for GATA1 levels. Supporting this idea, recent studies have revealed that GATA1 target genes show different sensitivities to tamoxifen-induced GATA1 [26]. The difference in sensitivity to GATA1 levels is also observed with Gata1 knockout and knockdown mice.…”

Controlling Hematopoiesis through Sumoylation-Dependent Regulation of a GATA Factor

“…Estradiol lacks activity in G1E cells devoid of ER-GATA-1, and estradiol-induced transcription in G1E-ER-GATA-1 cells reflects GATA-1 activity to control its physiological target genes (Johnson et al, 2007; Johnson et al, 2006; Welch et al, 2004). Even though the K137 mutants and ER-GATA-1 were expressed at comparable levels (Fig.…”

“…Knock-in mice bearing Ser to Ala mutations of two sites within the N-terminus (S72 and S142) and also S310 (Zhao et al, 2006) exhibit normal steady-state erythropoiesis and responsiveness to acute stress in vivo (Rooke and Orkin, 2006). Deletion of amino acids 1–193 differentially affects target gene expression in G1E cells (Johnson et al, 2006). Since the 1–193 deletion eliminates K137, and protein-protein interactions requiring amino acids 1–193 are unknown, K137 might confer functionality to this important region.…”

Emerging roles of the SUMO pathway in development

“…Specific GATA1 target genes are coregulated by FOG1 (e.g., b-globin, a-globin and Slc4a1) and others are controlled by an independent mechanism (e.g., Epb4.9, Fog1, and Eklf) [110,112]. The functional importance of the GATA1 N-terminus was previously determined [113,114]. A detailed analysis of significant residues in this region led to the identification of K137 as a sumoylation site [113].…”