TEA domain transcription factor 4 modulates repression of fetal haemoglobin by direct binding to the gamma-globin gene promoters

Re-activation of fetal haemoglobin (HbF) has been proved to be an effective strategy for the treatment of beta-haemoglobinopathies. In this study, we identified TEA domain transcription factor 4 (TEAD4) as a new potential regulator of HbF by integrating public data sets with quantitative polymerase chain reaction analysis in beta-thalassaemia patients. Significant negative correlation was observed between the expression of TEAD4 and HbF levels in beta-thalassaemia patients. Functional validations of TEAD4 inhibition in both beta-thalassaemia CD34(+) cells and HUDEP-2 cells indicated that depletion of TEAD4 led to a significant increase of HbF. Finally, we identified a binding motif of TEAD4 on gamma-globin gene promoters; its disruption consistently led to de-repression of HbF. Taken together, these results demonstrate that TEAD4 could act as a transcriptional inhibitor of the gamma-globin gene through direct binding on its promoter. Our findings demonstrate a novel role of TEAD4 on the regulation of HbF, which may benefit patients with beta-haemoglobinopathies.