Role of Sox6 and Coup-TFII transcription factors in the regulation of hemoglobin switching

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.