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Abstract

In humans, physiological hypoxia is the main driver for erythropoiesis. Hypoxia is sensed by kidney interstitial fibroblasts, which then secrete erythropoietin (EPO) to stimulate erythropoiesis in the bone marrow. In recent years, epigenetic mechanisms controlling erythropoiesis have attracted increasing attention. Recent advances in the field elucidated how epigenetic regulation contributes to maintenance of normal erythropoiesis, and how deregulation of the epigenetic machinery leads to abnormal differentiation of hematopoietic stem and progenitor cells, leading to hematopoietic malignancies. In particular, the covalent cytosine modification 5-hydroxymethylcytosine (5-hmC) is crucial for normal erythropoiesis. The enzymes that convert 5-methylcytosine (5-mC) into 5-hmC are the Ten-eleven translocation methylcytosine dioxygenases (TETs), which use oxygen and 2-oxoglutarate (2-OG) as additional substrates for the reaction and Fe(II) as a cofactor. However, it was not known how a hypoxic environment like the bone marrow regulates the TET genes and their transcripts. In my doctoral work, I investigated the effects of hypoxia on 5-hmC levels and distribution during erythropoiesis. My results showed that hypoxia induces 5-hmC accumulation despite low oxygen availability, and part of this effect is mediated through the direct upregulation of TET3 by HIF-1. In addition, I tested whether altering chromatin structure by inhibiting the bromodomain and extra-terminal (BET) proteins leads to re-expression of fetal and/or embryonic β-globin genes. My results showed that BET inhibition leads to downregulation of genes encoding suppressors of fetal or embryonic β-globin and disrupts the association of the enhancers with adult β-globin genes, resulting in re-activation of embryonic globins. This observation suggests that BET inhibitors could be useful in treating β-globinopathies like sickle cell anemia. Overall, my results regarding the epigenetic regulation of erythropoiesis have revealed previously unknown molecular mechanisms and provide novel strategies for the treatment of blood disorders.

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