Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes.
During development and erythropoiesis, globin gene expression is finely modulated through an important network of transcription factors and chromatin modifying activities. In this report we provide in vivo evidence that endogenous Ikaros is recruited to the human beta-globin locus and targets the histone deacetylase HDAC1 and the chromatin remodeling protein Mi-2 to the human gamma-gene promoters, thereby contributing to gamma-globin gene silencing at the time of the gamma- to beta-globin gene transcriptional switch. We show for the first time that Ikaros interacts with GATA-1 and enhances the binding of the latter to different regulatory regions across the locus. Consistent with these results, we show that the combinatorial effect of Ikaros and GATA-1 impairs close proximity between the locus control region and the human gamma-globin genes. Since the absence of Ikaros also affects GATA-1 recruitment to GATA-2 promoter, we propose that the combinatorial effect of Ikaros and GATA-1 is not restricted to globin gene regulation.
Bottardi
Stefania
S
Maisonneuve Rosemont Hospital Research Center, Maisonneuve-Rosemont Hospital, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
Ross
Julie
J
Bourgoin
Vincent
V
Fotouhi-Ardakani
Nasser
N
Affar
El Bachir
el B
Trudel
Marie
M
Milot
Eric
E
D000818:Animals; D004920:Erythropoiesis / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism*
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; C497239:IKZF1 protein, human; C497238:Zfpn1a1 protein, mouse; D055545:gamma-Globins; D051740:Ikaros Transcription Factor; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases