| Summary: | 博士 === 國立陽明大學 === 生命科學暨基因體科學研究所 === 98 === The mammalian embryonic globin genes, including that of the humans, are expressed at the early embryonic stage and then switched off during erythroid development. This autonomous silencing of the ? globin gene transcription is likely regulated by the co-operative works among various protein -DNA and protein-protein complexes formed at the ? globin promoter and its upstream enhancer (HS-40). I present data here that a protein-binding motif, ZF2, contributes to the repression of the HS-40 regulated human ? promoter activity in erythroid cell lines and in transgenic mice.
Combined site-directed mutagenesis and electrophoretic mobility shift assay (EMSA) suggest that repression of the human ? globin promoter is mediated through binding of the zinc-finger factor RREB1 to ZF2. This model is further supported by the observation that the human ? globin gene transcription is elevated in human erythroid K562 cell line or the primary erythroid culture upon RNAi knock-down of RREB1 expression. Interestingly, RREB1 also behaved as a repressor of the ε globin gene transcription. These data together suggest that RREB1 is a putative repressor for the silencing of the mammalian ? globin genes during erythroid development.
Since ζ globin is a powerful inhibitor of HbS polymerization, the experiments here have provided a foundation for therapeutic upregulation of ζ globin gene expression in patients with severe hemoglobinopathies.
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