The roles of the transcription factor B-cell CLL/Lymphoma 11A (BCL11A) in erythroid cells

Abstract

Haemoglobin is a key protein component of erythroid cells and is involved in transporting oxygen through the bloodstream. The protein subunits that make up haemoglobin are expressed from the α-globin and β-globin loci. Different forms of haemoglobin are expressed at different developmental stages in order to meet differing oxygen demands during development. The process of switching from expression of embryonic to foetal to adult haemoglobin is known as ‘globin switching’. β-haemoglobinopathies result from mutations within the adult β-globin gene. The symptoms of these disorders could be ameliorated by elevating foetal haemoglobin protein (HbF) after birth in affected individuals. Thus, understanding the molecular mechanism underlying globin switching is important to allowing development of β-haemoglobinopathy therapeutics. B-cell CLL/Lymphoma 11A (BCL11A) is a multi-zinc finger transcription factor that plays a key role in silencing γ-globin, the foetal β-globin gene. However, the molecular mechanism by which BCL11A silences γ-globin has remained elusive. This study initially aimed to investigate direct binding of BCL11A to the γ-globin proximal promoter region in vivo using a novel BCL11A-ER-V5 inducible model. We were able to demonstrate, for the first time, that BCL11A represses γ-globin by binding directly to the proximal promoter region of γ-globin. As elevating the expression level of HbF can ameliorate the symptoms of β-globin disorders, our findings shed light on a new therapeutic strategy for β-globin disorders. We investigated BCL11A regulated genes by RNA-Seq and discovered that human BCL11A has potential roles in maintaining erythroid progenitors and lineage commitment. In order to further characterise how BCL11A regulates target genes, we studied the binding mechanism of BCL11A to the γ-globin promoter and other target genes promoter regions in erythroid cells. We defined the binding consensus motif of BCL11A in vivo and uncovered distinct binding patterns of BCL11A at different target genes. These findings help us to better understand the binding mechanism of BCL11A in erythroid cells and suggest that BCL11A may play potential roles in maintenance of the homeostasis of erythroid cells. We propose that an alternative strategy to modulation of BCL11A expression for elevation of HbF that may yield fewer side-effects is to directly disrupt the binding site of BCL11A at the γ-globin proximal promoter region.