Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF
Lethal β-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF
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DOI：
10.1038/375318a0
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发表时间：
1995-05
期刊：
影响因子：
64.8
通讯作者：
A. Parkins;A. Sharpe;S. Orkin
中科院分区：
文献类型：
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作者：
A. Parkins;A. Sharpe;S. Orkin
珠蛋白基因以组织特异性和发育阶段特异性的方式进行调控，β-珠蛋白基因是β基因簇1中最后被激活的基因。CACCC-核苷酸序列与多种核蛋白结合，包括普遍表达的SPL和红系Krüppel样因子(EKLF)，是珠蛋白和非珠蛋白红系表达基因2-5转录的关键调控序列。为了确定EKLF在体内的功能，我们通过基因打靶6创造了EKLF缺陷的小鼠。这些胚胎在胎肝红细胞生成过程中死于贫血，表现出β-珠蛋白缺乏症的分子和血液学特征，发现于β-地中海贫血症。虽然EKLF在所有发育阶段都有表达，但它不是卵黄囊红细胞生成、红系承诺或其他潜在靶基因表达所必需的。它的阶段特异性和β-珠蛋白基因特异性的要求表明，EKLF可能有助于完成人类从胎儿到成人(血红蛋白α到β)的转换。
GLOBIN genes are regulated in a tissue-specific and developmental stage-specific manner, with the β-globin gene being the last to be activated in the β-gene cluster1. CACCC-nucleotide sequences, which bind multiple nuclear proteins, including ubiquitously expressed Spl and erythroid Krüppel-like factor (EKLF), are among thecis-regulatory sequences critical for transcription of globin and non-globin erythroid-expressed genes2-5. To determine the function of EKLFin vivo, we created mice deficient in EKLF by gene targeting6. These embryos die of anaemia during fetal liver erythropoiesis and show the molecular and haematological features of β-globin deficiency, found in β-thalassaemia. Although it is expressed at all stages, EKLF is not required for yolk sac erythropoiesis, erythroid commitment or expression of other potential target genes. Its stage-specific and β-globin-gene-specific requirement suggests that EKLF may facilitate completion of the fetal-to-adult (haemoglobin α to β) switch in humans.