Control of globin gene expression by Kruppel-like factors

Abstract

Kruppel-like factors (KLFs) are a family of seventeen proteins designated KLF1 to KLF17. KLFs are transcriptional factors that bind GC-rich sequences such as CACCC elements. The DNA binds to KLFs via three carboxyl-terminal Cys-2/His-2 zinc fingers. KLFs control cell differentiation and embryonic development. They are also implicated in a number of cellular functions such as erythropoiesis, proliferation and tissue development. This review will focus primarily on KLFs that are involved in haemoglobin control. These include KLF1, KLF2, KLF3, KLF8 and KLF10. The connection between human KLF1 and elevated foetal haemoglobin was first identified in a study done by Borg et al (2010) on a large Maltese family with Hereditary Persistence of Foetal Haemoglobin (HPFH) where a nonsense mutation in the Erythroid Kruppel-Like Factor 1 gene (KLF1) was identified as the main cause of HPFH. KLF2 is a positive regulator of mouse and human embryonic beta-globin genes and it overlaps with KLF1 in embryonic erythropoiesis. KLF3 and KLF8 expression is driven by KLF1 while together KLF3 and KLF8 participate in the silencing of embyronic globin expression during development. KLF10 expression was also shown to be associated with high foetal haemoglobin levels in beta-thalassaemia patients undergoing hydroxyurea treatment.