Several transcription factors are essential for erythroid commitment and for differential globin gene expression during development. Sox6 and COUP-TFII are important Transcription Factors that are known to be modulators of globins genes regulation. By using a variant erythroleukemic cell line (V-K562) expressing both γ- and β- globins, we show how Sox6 and COUP-TFII are able to differentially regulate fetal versus adult globin genes. Both Sox6 and COUP-TFII binds in vitro and in vivo to the γ-globin promoter. Lentiviral mediated overexpression of Sox6 in this variant cells predominantly increases β-globin expression while COUP-TFII overexpression increases level of γ-globin expression. Co-transduction of Sox6 and COUP-TFII at different levels proportionately alters the balance between γ- and the β-globin expression suggesting that their differential expression could able to influence the switch. In line with these results, mouse embryonic fetal liver cells during the switching time (from E 11.5-13.5) show an increase in the level of Sox6 during development and a parallel decrease in the level of COUP-TFII expression. Preliminary experiments in human erythroid cultures from peripheral blood indicate that at low levels of COUP-TFII transduced cells, COUP-TFII overexpression increases the γ-globin expression level indicating COUP-TFII as a prospective target whose modulation can increase γ-globin expression.
(2014). Role of Sox6 and Coup-TFII transcription factors in the regulation of hemoglobin switching. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2014).
Role of Sox6 and Coup-TFII transcription factors in the regulation of hemoglobin switching
ELANGOVAN, SUDHARSHAN
2014
Abstract
Several transcription factors are essential for erythroid commitment and for differential globin gene expression during development. Sox6 and COUP-TFII are important Transcription Factors that are known to be modulators of globins genes regulation. By using a variant erythroleukemic cell line (V-K562) expressing both γ- and β- globins, we show how Sox6 and COUP-TFII are able to differentially regulate fetal versus adult globin genes. Both Sox6 and COUP-TFII binds in vitro and in vivo to the γ-globin promoter. Lentiviral mediated overexpression of Sox6 in this variant cells predominantly increases β-globin expression while COUP-TFII overexpression increases level of γ-globin expression. Co-transduction of Sox6 and COUP-TFII at different levels proportionately alters the balance between γ- and the β-globin expression suggesting that their differential expression could able to influence the switch. In line with these results, mouse embryonic fetal liver cells during the switching time (from E 11.5-13.5) show an increase in the level of Sox6 during development and a parallel decrease in the level of COUP-TFII expression. Preliminary experiments in human erythroid cultures from peripheral blood indicate that at low levels of COUP-TFII transduced cells, COUP-TFII overexpression increases the γ-globin expression level indicating COUP-TFII as a prospective target whose modulation can increase γ-globin expression.File | Dimensione | Formato | |
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PhD_Unimib_745216.pdf
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