Specification of hematopoietic and vascular development by the bHLH transcription factor SCL without direct DNA binding.
Specification of hematopoietic and vascular development by the bHLH transcription factor SCL without direct DNA binding.
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发表时间：
1999-10
期刊：
影响因子：
4.6
通讯作者：
C. Porcher;Eric C. Liao;Y. Fujiwara;Leonard I. Zon;Stuart H. Orkin
中科院分区：
文献类型：
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作者：
C. Porcher;Eric C. Liao;Y. Fujiwara;Leonard I. Zon;Stuart H. Orkin
转录因子，如碱性螺旋环螺旋（bHLH）和同源结构域类的转录因子，是细胞命运决定和分化的主要调节因子。它们通过直接结合关键靶基因中的同源DNA序列来控制各自的发育程序被认为是不言自明的。在这里，我们测试这一广泛持有的范式，在体内功能测定白血病癌蛋白SCL，bHLH因子，类似于肌源性和神经源性蛋白质，是必不可少的造血和血管发育的脊椎动物。与所有预期相反，我们发现SCL变体不能结合DNA，从基因靶向的SCL（-）（/）（-）胚胎干细胞中拯救造血，并补充斑马鱼突变钟状体中的造血和血管缺陷。我们的研究结果建立DNA结合独立的功能SCL转录规范的关键，并应鼓励重新评估推定的要求，直接DNA结合的其他转录因子在启动的发展计划。
Transcription factors, such as those of the basic-helix-loop-helix (bHLH) and homeodomain classes, are primary regulators of cell fate decisions and differentiation. It is considered axiomatic that they control their respective developmental programs via direct binding to cognate DNA sequences in critical targets genes. Here we test this widely held paradigm by in vivo functional assay of the leukemia oncoprotein SCL, a bHLH factor that resembles myogenic and neurogenic proteins and is essential for both hematopoietic and vascular development in vertebrates. Contrary to all expectation, we find that SCL variants unable to bind DNA rescue hematopoiesis from gene-targeted SCL(-)(/)(-) embryonic stem cells and complement hematopoietic and vascular deficits in the zebrafish mutant cloche. Our findings establish DNA-binding-independent functions of SCL critical for transcriptional specification, and should encourage reassessment of presumed requirements for direct DNA binding by other transcription factors during initiation of developmental programs.