Heme synthesis is regulated in a highly tissue-specific manner. In particular, erythroid heme synthesis is regulated either by the erythroid-specific isozymes, or by upregulation of the erythroid-specific delta-aminolevulinate (ALA) synthase (ALAS2) by heme, the end-product of the heme biosynthetic pathway, while hepatic heme synthesis is downregulated by heme at the level of the non-specific delta-aminolevulinate (ALA) synthase (ALAS1).
The specific aim of this study is to define the nature of the erythroid- specific control of heme synthesis and the role of heme in gene expression in erythroid cells. The focus will be placed on the role of NF-E2, the erythroid transcription factor, on erythroid gene expression, and the erythroid heme pathway gene expression, especially that of ALAS2, on erythroid differentiation. The investigators plan to examine the regulation of NF-E2 activity in erythroid differentiation and the regulation of the human ALAS (hALAS2) gene expression. These studies will hopefully clarify the role of ALAS2 and transcription factors such as NF-E2 and Bach1 in erythroid differentiation, and shed light on the distinct aspects of erythroid heme synthesis.
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