KLF1 in Erythroid Differentiation: An essential transcription factor in health and disease

markdownabstractβ-thalassemia and sickle cell disease, along with α-thalassemia, are the most common monogenic disorders, with approximately 300.000 affected children born each year. The observation that increased γ-globin expression can ameliorate the symptoms of these diseases eventually led to the discovery of the first treatments, mainly hydroxyurea-mediated induction of γ-globin express ion. However, hudroxyurea is effective in only 50% of the SCD patients. Therefore, current research focuses on finding new strategies to increase fetal γ-globin induction that could be utilized to complement defective adult globin in the aforementioned diseases. Understanding the exact mechanisms driving the globin switch will help in the development of new therapeutics. However, despite increasing knowledge of how the globin genes are modulated, a comprehensive picture of these mechanism is still missing. KLFl undoubtedly constitutes one of the major regulators of erythropoiesis, but although it has been investigated for more than 20 year, its precise role in fine-tuning erythroid maturation is still elusive. In the experimental Chapters 2 to 5, I present our work, aiming to provide in­ depth insight on how KLFl modulates diverse processes to control erythropoiesis. In particular, in Chapter 2 I show our results on the interplay between KLFl and BCL11A in adult erythropoiesis and globin regulation. Taking advantage of the KLFl Nan mutant, we were able to identify new potential KLFl target genes with a possible role in erythropoiesis. More specifically, in Chapter 3 I describe the effects of the KFLl Nan mutation during embryonic development, focusing in particular on the role of the exportin XP07 in causing the overall phenotype, while in Chapter 4 I describe our initial observation of a potential, unexpected role of KLFl in regulating the function of the Golgi apparatus via BSDCl. Finally, identifying KLFl binding partners would be a great step towards elucidating its multifaceted role in globin switching and erythropoiesis. Our ongoing efforts to obtain a comprehensive list of such KLF1-interacting partners by mass-spectrometry analysis of pulled­ down KLFl complexes are described in Chapter 5