GATA1 and YY1 are developmental repressors of the human epsilon‐globin gene

• Published in: The EMBO journal Vol. 14; no. 4; pp. 801 - 809
• Main Authors: Raich, N., Clegg, C.H., Grofti, J., Roméo, P.H., Stamatoyannopoulos, G.
• Format: Journal Article
• Language: English
• Published: England 15.02.1995
• Subjects: Animals; Base Sequence; DNA; DNA Primers - chemistry; DNA-Binding Proteins - physiology; enhancers; epsilon chain; Erythroid-Specific DNA-Binding Factors; Erythropoiesis; GATA-1 protein; GATA1 Transcription Factor; Gene Expression Regulation, Developmental; Globins - genetics; hemoglobin; Humans; locus control region; man; Mice; Mice, Transgenic; Molecular Sequence Data; Promoter Regions, Genetic; promoters; Repressor Proteins - genetics; RNA, Messenger - genetics; silencers; transcription factors; Transcription Factors - physiology; transgenic mice; YY1 protein; YY1 Transcription Factor
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/j.1460-2075.1995.tb07058.x

The human epsilon‐globin gene is transcribed in erythroid cells only during the embryonic stages of development. Expression of epsilon‐globin gene, however, can be maintained in adult transgenic mice following removal of DNA positioned between ‐467 and ‐182 bp upstream of the epsilon‐globin cap site. We have identified three protein binding regions within this silencer; a CCACC motif around ‐379, two overlapping motifs for YY1 and GATA around ‐269 and a GATA motif around ‐208 and we have analyzed their function during development by studying several mutants in transgenic mice. Mutation of the ‐208 GATA motif allows high epsilon‐globin transgene expression in the adult suggesting that, in addition to its positive effects on transcription, GATA‐1 also plays a negative role in the regulation of globin gene expression during development. Repression of epsilon gene expression in the adult also requires a functional YY1 binding site at position ‐269. Finally, mutation of the ‐379 CCACC site results in a small but detectable level of epsilon expression in adult erythroid cells. Thus, multiple proteins, including GATA‐1, participate in the formation of the epsilon gene repressor complex that may disrupt the interaction between the proximal epsilon‐promoter and the locus control region (LCR) in definitive erythroid cells.