title: GATA1 and YY1 are developmental repressors of the human epsilon-globin gene.
abstract: 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.
authors.affiliation: INSERM U91, Hôpital Henri Mondor, Créteil, France.
authors.forename: N
authors.initials: N
authors.lastname: Raich
authors.forename: C H
authors.initials: CH
authors.lastname: Clegg
authors.forename: J
authors.initials: J
authors.lastname: Grofti
authors.forename: P H
authors.initials: PH
authors.lastname: Roméo
authors.forename: G
authors.initials: G
authors.lastname: Stamatoyannopoulos
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis; D050982:GATA1 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D005914:Globins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D050986:YY1 Transcription Factor
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C494699:Yy1 protein, mouse; D005914:Globins