SCL assembles a multifactorial complex that determines glycophorin A expression
SCL assembles a multifactorial complex that determines glycophorin A expression
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DOI：
10.1128/mcb.24.4.1439-1452.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Hoang, T
中科院分区：
文献类型：
--
作者：
Lahlil, R;Lécuyer, E;Hoang, T
SCL/TAL1是碱性螺旋 - 环 - 螺旋（bHLH）家族的一种造血特异性转录因子，对红细胞生成至关重要。在此，我们确定红系细胞特异性血型糖蛋白A基因（GPA）是原代造血细胞中SCL的一个靶标，并表明SCL在体内占据GPA基因座。GPA启动子的激活依赖于一个包含SCL以及普遍存在的（E47、Sp1和Ldb1）和组织特异性（LMO2和GATA - 1）转录因子的多因子复合物的组装。此外，我们的观察结果表明该复合物内存在功能特化，因为SCL提供其HLH蛋白相互作用基序，GATA - 1通过其与GPA启动子中一个关键的GATA元件结合而发挥DNA连接功能，并且E47需要其N末端部分（很可能涉及一种反式激活功能）。最后，当E47的一种截短形式（E47 - bHLH）对E蛋白活性产生显性抑制作用，或者FOG（GATA的朋友）对GATA活性产生抑制作用，或者LMO2或Ldb - 1蛋白水平降低时，造血细胞中的内源性GPA表达会被破坏。总之，这些观察结果揭示了SCL复合物内转录因子的功能互补性，以及SCL作为激活GPA基因表达所需的高阶复合物中的成核因子的关键作用。
SCL/TAL1 is a hematopoietic-specific transcription factor of the basic helix-loop-helix (bHLH) family that is essential for erythropoiesis. Here we identify the erythroid cell-specific glycophorin A gene (GPA) as a target of SCL in primary hematopoietic cells and show that SCL occupies the GPA locus in vivo. GPA promoter activation is dependent on the assembly of a multifactorial complex containing SCL as well as ubiquitous (E47, Sp1, and Ldb1) and tissue-specific (LMO2 and GATA-1) transcription factors. In addition, our observations suggest functional specialization within this complex, as SCL provides its HLH protein interaction motif, GATA-1 exerts a DNA-tethering function through its binding to a critical GATA element in the GPA promoter, and E47 requires its N-terminal moiety (most likely entailing a transactivation function). Finally, endogenous GPA expression is disrupted in hematopoietic cells through the dominant-inhibitory effect of a truncated form of E47 (E47-bHLH) on E-protein activity or of FOG (Friend of GATA) on GATA activity or when LMO2 or Ldb-1 protein levels are decreased. Together, these observations reveal the functional complementarities of transcription factors within the SCL complex and the essential role of SCL as a nucleation factor within a higher-order complex required to activate gene GPA expression.