High levels of human gamma-globin gene expression in adult mice carrying a transgene of deletion-type hereditary persistence of fetal hemoglobin.
High levels of human gamma-globin gene expression in adult mice carrying a transgene of deletion-type hereditary persistence of fetal hemoglobin.
复制标题
在携带胎儿血红蛋白缺失型遗传性持久性转基因的成年小鼠中，人类伽马珠蛋白基因表达水平较高。
DOI：
10.1128/mcb.17.4.2076
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发表时间：
1997
影响因子：
5.3
通讯作者：
Forget,BG
中科院分区：
文献类型：
--
作者：
Arcasoy,MO;Romana,M;Fabry,ME;Skarpidi,E;Nagel,RL;Forget,BG
Persistent expression of the γ-globin genes in adults with deletion types of hereditary persistence of fetal hemoglobin (HPFH) is thought to be mediated by enhancer-like effects of DNA sequences at the 3′ breakpoints of the deletions. A transgenic mouse model of deletion-type HPFH was generated by using a DNA fragment containing both human γ-globin genes and HPFH-2 breakpoint DNA sequences linked to the core sequences of the locus control region (LCR) of the human β-globin gene cluster. Analysis of γ-globin expression in six HPFH transgenic lines demonstrated persistence of γ-globin mRNA and peptides in erythrocytes of adult HPFH transgenic mice. Analysis of the hemoglobin phenotype of adult HPFH transgenic animals by isoelectric focusing showed the presence of hybrid mouse α2-human γ2tetramers as well as human γ4homotetramers (hemoglobin Bart’s). In contrast, correct developmental regulation of the γ-globin genes with essentially absent γ-globin gene expression in adult erythroid cells was observed in two control non-HPFH transgenic lines, consistent with autonomous silencing of normal human γ-globin expression in adult transgenic mice. Interestingly, marked preferential overexpression of the LCR-distalAγ-globin gene but not of the LCR-proximalGγ-globin gene was observed at all developmental stages in erythroid cells of HPFH-2 transgenic mice. These findings were also associated with the formation of a DNase I-hypersensitive site in the HPFH-2 breakpoint DNA of transgenic murine erythroid cells, as occurs in normal human erythroid cells in vivo. These results indicate that breakpoint DNA sequences in deletion-type HPFH-2 can modify the developmentally regulated expression of the γ-globin genes.
