NF-Y recruits both transcription activator and repressor to modulate tissue- and developmental stage-specific expression of human γ-globin gene.
The human embryonic, fetal and adult β-like globin genes provide a paradigm for tissue- and developmental stage-specific gene regulation. The fetal γ-globin gene is expressed in fetal erythroid cells but is repressed in adult erythroid cells. The molecular mechanism underlying this transcriptional switch during erythroid development is not completely understood. Here, we used a combination of in vitro and in vivo assays to dissect the molecular assemblies of the active and the repressed proximal γ-globin promoter complexes in K562 human erythroleukemia cell line and primary human fetal and adult erythroid cells. We found that the proximal γ-globin promoter complex is assembled by a developmentally regulated, general transcription activator NF-Y bound strongly at the tandem CCAAT motifs near the TATA box. NF-Y recruits to neighboring DNA motifs the developmentally regulated, erythroid transcription activator GATA-2 and general repressor BCL11A, which in turn recruit erythroid repressor GATA-1 and general repressor COUP-TFII to form respectively the NF-Y/GATA-2 transcription activator hub and the BCL11A/COUP-TFII/GATA-1 transcription repressor hub. Both the activator and the repressor hubs are present in both the active and the repressed γ-globin promoter complexes in fetal and adult erythroid cells. Through changes in their levels and respective interactions with the co-activators and co-repressors during erythroid development, the activator and the repressor hubs modulate erythroid- and developmental stage-specific transcription of γ-globin gene.
Department of Biochemistry and Molecular Biology, Medical College of Georgia and College of Graduate Studies, Georgia Health Sciences University, Augusta, GA, USA.
Xingguo
X
Zhu
Yongchao
Y
Wang
Wenhu
W
Pi
Hui
H
Liu
Amittha
A
Wickrema
Dorothy
D
Tuan
D001483:Base Sequence; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D020014:K562 Cells; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps; D012097:Repressor Proteins; D016385:TATA Box; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
C486563:BCL11A protein, human; D023081:CCAAT-Binding Factor; D002352:Carrier Proteins; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D050989:GATA2 Transcription Factor; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055545:gamma-Globins