Promoter assays of the human KLF1 gene

Abstract

Hereditary persistence of foetal haemoglobin (HPFH) is a rare hereditary condition resulting in elevated levels of foetal haemoglobin (HbF) in adults. Typical HPFH is associated with promoter mutations or large deletions affecting the human foetal globin (HBG1 and HBG2) genes, while genetic defects in other genes involved in human erythropoiesis, e.g. KLF1, also result in atypical HPFH. Here, we report the four different KLF1 gene promoter mutations that have been uncovered through a population screen in Malta conducted on human subjects with borderline haematological parameters (HbA2 and HbF) and are being associated with increased HbF level and decreased KLF1 promoter activity. These mutations were shown to result a significant downregulation of the KLF1 promoter activity (> 2-fold difference) In silico analysis showed that the mutations under study occupy important cis- sequences that are required for the normal expression of the KLF1 transcript and are also attracting transcription factors whose binding might be affected. This data strongly suggests that the KLF1 promoter mutations under study, could play a role in increasing HbF or HbA2 levels in adults and further underlines the role of KLF1 as one of the key transcription factors involved in human foetal to adult globin gene switching.