Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes
Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes
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DOI：
10.1016/j.ydbio.2008.10.044
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发表时间：
2009-03-15
影响因子：
2.7
通讯作者：
Becker, Thomas S.
中科院分区：
文献类型：
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作者：
Navratilova, Pavia;Fredman, David;Becker, Thomas S.
泛脊椎动物发育顺式调控元件是可辨别的高度保守的非编码元件（HCNEs），并经常分散在周围的多效性基因的表达，他们控制的大面积。在两个发育转录因子基因SOX 3和PAX 6的位点上，我们证明了人类和斑马鱼之间保守的HCNE可以系统地和可靠地测试它们在斑马鱼中的多个稳定转基因中的调节功能，并且它们的基因组范围使用同线性保守和HCNE密度沿着这些位点进行置信度估计。人类和斑马鱼的HCNE在斑马鱼中作为特异性发育增强剂发挥作用。我们表明，人类HCNEs导致斑马鱼中的表达模式相当于小鼠中的表达模式，从而建立了斑马鱼作为大规模测试人类发育增强剂的合适模型。正交的人类和斑马鱼增强子在其序列内经历功能进化，并且通常指导相关但不相同的表达模式。尽管有4.5亿年的进化距离，但在比较斑马鱼与人类HCNE时，一个pax6 HCNE在相同的区域驱动表达。来自同一区域的HCNE通常驱动重叠模式，这表明需要多个调控输入来实现发育基因所表现出的稳健和精确的复杂表达模式。(C)2008年爱思唯尔公司All rights reserved.
Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. On the loci of two developmental transcription factor genes, SOX3 and PAX6, we demonstrate that HCNEs conserved between human and zebrafish can be systematically and reliably tested for their regulatory function in multiple stable transgenes in zebrafish, and their genomic reach estimated with confidence using synteny conservation and HCNE density along these loci. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. We show that human HCNEs result in expression patterns in zebrafish equivalent to those in mouse, establishing zebrafish as a suitable model for large-scale testing of human developmental enhancers. Orthologous human and zebrafish enhancers underwent functional evolution within their sequence and often directed related but non-identical expression patterns. Despite an evolutionary distance of 450 million years, one pax6 HCNE drove expression in identical areas when comparing zebrafish vs. human HCNEs. HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes. (C) 2008 Elsevier Inc. All rights reserved.