Global regulation of erythroid gene expression by transcription factor GATA-1

• Published in: Blood Vol. 104; no. 10; pp. 3136 - 3147
• Main Authors: Welch, John J., Watts, Jason A., Vakoc, Christopher R., Yao, Yu, Wang, Hao, Hardison, Ross C., Blobel, Gerd A., Chodosh, Lewis A., Weiss, Mitchell J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.11.2004; The Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - genetics; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic - physiology; Erythroblasts - cytology; Erythroblasts - physiology; Erythroid-Specific DNA-Binding Factors; Erythropoiesis - genetics; Fundamental and applied biological sciences. Psychology; GATA1 Transcription Factor; Gene Expression Profiling; Genetic Complementation Test; Humans; Mice; Molecular and cellular biology; Nuclear Proteins - genetics; Reproducibility of Results; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - physiology; Erythropoiesis; Human; Stem cell; Transcriptome; Hematopoietic cell; Red blood cell; Cell differentiation; Gene expression; Signal transduction; Blood cell; Regulation(control); Hematopoiesis; Transcription factor; Transcription factor GATA1
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-04-1603

Transcription factor GATA-1 is required for erythropoiesis, yet its full actions are unknown. We performed transcriptome analysis of G1E-ER4 cells, a GATA-1–null erythroblast line that undergoes synchronous erythroid maturation when GATA-1 activity is restored. We interrogated more than 9000 transcripts at 6 time points representing the transition from late burst forming unit–erythroid (BFU-E) to basophilic erythroblast stages. Our findings illuminate several new aspects of GATA-1 function. First, the large number of genes responding quickly to restoration of GATA-1 extends the repertoire of its potential targets. Second, many transcripts were rapidly down-regulated, highlighting the importance of GATA-1 in gene repression. Third, up-regulation of some known GATA-1 targets was delayed, suggesting that auxiliary factors are required. For example, induction of the direct GATA-1 target gene β major globin was late and, surprisingly, required new protein synthesis. In contrast, the gene encoding Fog1, which cooperates with GATA-1 in β globin transcription, was rapidly induced independently of protein synthesis. Guided by bioinformatic analysis, we demonstrated that selected regions of the Fog1 gene exhibit enhancer activity and in vivo occupancy by GATA-1. These findings define a regulatory loop for β globin expression and, more generally, demonstrate how transcriptome analysis can be used to generate testable hypotheses regarding transcriptional networks.