Developmental regulation of human globin genes in transgenic mice.
Developmental regulation of human globin genes in transgenic mice.
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转基因小鼠中人珠蛋白基因的发育调控。
DOI：
10.1101/sqb.1985.050.01.046
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Chada,K
中科院分区：
文献类型：
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作者：
Costantini,F;Radice,G;Magram,J;Stamatoyannopoulos,G;Papayannopoulou,T;Chada,K
珠蛋白基因家族是研究发育基因调控的一个特别有趣的系统。珠蛋白基因不仅在红系细胞中特异性表达，而且该基因家族的不同成员在发育的连续阶段被利用，这种现象被称为”血红蛋白转换“。“在人类编码/S样链的基因中，首先表达的是e-珠蛋白基因，它主要在卵黄囊血岛中发育的原始红细胞中活跃。在妊娠第5周和第10周之间，有一个”确定的”胎肝红细胞生成的转变，在此期间，e基因被关闭，两个~，-珠蛋白基因开始表达。7-珠蛋白基因在胎儿生命的大部分时间内最活跃，并在出生时关闭。相比之下，”成人”基因6和3在胎儿肝脏红系细胞中仅以低水平活跃，并且仅在出生后才完全开启，因为红细胞生成的位点从肝脏转移到骨髓（Weatherall和Clegg 1981）。所有的类人珠蛋白基因都位于一个簇中（图1），并按其表达顺序排列在5 '到3'端（Fritsch et al.1980）。最近，在理解红系细胞分化过程中成人β-珠蛋白基因转录被激活的机制方面取得了一些进展。这似乎是一个多步骤的过程，在基因真正转录之前就开始了（Stalder et al. 1980 a; Cohen and Sheffery 1985; Yu and Smith 1985）。最早期的事件可能涉及染色质结构、甲基化模式或尚未确定的基因性质的变化，这些事件似乎是转录所必需的，但不是充分的（Groudine and Weintraub 1982;沙尔奈et al. 1984; Yu and Smith 1985）。允许转录的后期事件可能涉及β-珠蛋白基因与分化红系细胞特异性反式作用因子的相互作用（Chao等，1983; Wright等，1983; Emerson等，1985）。通过使用培养的红系细胞系如鼠红白血病（MEL）细胞的基因转移实验，已经有可能开始确定似乎与成人红系细胞中的反式作用调节因子相互作用的DNA序列。现有数据表明，在红系分化的终末事件期间，起始密码子的5 '和3'端的多个序列参与调节转录（沙尔奈等人，1984; Wright等人，1984）。事实上，对基因激活的早期步骤的控制一无所知，并且由于转染到培养细胞中的克隆基因显然绕过了这些早期调节事件（Robins et al. 1982;沙尔奈et al. 1984），因此使用MEL或其他培养细胞不能容易地解决这个问题。
The globin gene family represents a particularly interesting system for the study of developmental gene regulation. Not only are the globin genes expressed specifically in erythroid cells, but different members of the gene family are utilized at sequential stages of development, a phenomenon known as" hemoglobin switching." Of the genes encoding/S-like chains in the human, the first to be expressed is the e-globin gene, which is active primarily in the primitive erythroid cells that develop in the blood islands of the yolk sac. Between the 5th and 10th weeks of gestation, there is a shift to" definitive" fetal liver erythropoiesis, and during this time the e gene is switched off and the two~,-globin genes begin to be expressed. The 7-globin genes are maximally active through most of fetal life and are switched off around the time of birth. In contrast, the" adult" genes, 6 and~ 3, are active at only a low level in the fetal liver erythroid cells and are turned on fully only after birth, as the site of erythropoiesis shifts from liver to bone marrow (Weatherall and Clegg 1981). All of the human~-like globin genes are located in a single cluster (Fig. l) and are arranged 5'to 3'in the order of their expression (Fritsch et al. 1980). Recently, there has been some progress in understanding the mechanism by which transcription of the adult/~-globin gene is activated during erythroid cell differentiation. This appears to be a multistep process that is initiated before the gene is actually transcribed (Stalder et al. 1980a; Cohen and Sheffery 1985; Yu andSmith 1985). The earliest events, which may involve changes in chromatin structure, in methylation patterns, or in as yet undefined properties of the gene, appear to be necessary but not sufficient for transcription (Groudine and Weintraub 1982; Charnay et al. 1984; Yu and Smith 1985). The later events, which permit transcription, probably involve the interaction of the/3-globin gene with trans-acting factors specific to differentiated erythroid cells (Chao et al. 1983; Wright et al. 1983; Emerson et al. 1985). Through gene transfer experiments using cultured erythroid cell lines, such as murine erythroleukemia (MEL) cells, it has been possible to begin to define the DNA sequences that appear to interact with trans-acting regulatory factors in adult erythroid cells. The available data indicate that multiple sequences, both 5'and 3'to the initiation codon, are involved in regulating transcription during the terminal events of erythroid differentiation (Charnay et al. 1984; Wright et al. 1984). Virtually nothing is known about the control of the earlier steps in gene activation, and since cloned genes transfected into cultured cells apparently bypass these early regulatory events (Robins et al. 1982; Charnay et al. 1984), the question cannot be readily addressed using MEL or other cultured cells.