The red blood cell or erythrocyte is the most abundant cell type in the blood circulation. This cell type is highly specialized to carry out its main function: the transport of oxygen from the lungs to the other parts of the body and the transport of carbon dioxide from these tissues back to the lungs. The binding and exchange of gas molecules is achieved by hemoglobin, a complex composed of four protein chains: two α-like and two β-like globin proteins and four heme molecules that bind oxygen.
Diseases affecting erythrocyte function are often a result of mutations in the β-globin gene, like in β-thalassemia and sickle cell anemia (SCA). The effects of β-thalassemia and sickle cell anemia are greatly ameliorated by expression of the γ-globin genes that are normally only expressed during the fetal stage of development. This is the primary reason that the disease only manifests itself after birth when globin gene expression switches from the normal γ-globin genes to the defective β-globin gene. As most β-thalassemia and SCA patients have a normal γ-globin gene, they are theoretically carriers of their own medicine: when the γ-globin gene is ‘reactivated’, it will compensate for the defective β-globin. We aim to understand how globin switching is regulated at the molecular level, with the long-term goal to reverse this process. This Landsteiner grant made it possible to study different aspects of globin switching. We studied the cooperation of the 2 main γ-like globin gene regulators: BCL11A and KLF1. We also studied the effect of one specific KLF1 mutation. Furthermore, we found that ZFP148 interacts with the γ-globin gene. To identify novel globin gene regulators, we compared the gene expression profiles of adult blood cells (low γ-globin) and fetal liver blood cells (high γ-globin). This, in combination with additional experiments resulted in a list of 24 candidate γ-globin repressors. Of these, 7 proteins were indeed shown to regulate γ-globin levels. Currently, 2 candidates are studied in more detail.

Thesis 2015: KLF1 in Erythroid Differentiation. An essential transcription factor in health and disease, Ilieana Cantu