Brody Thomas, Rasband Wayne, Baler Kevin, Kuzin Alexander, Kundu Mukta, Odenwald Ward F
Neural Cell-Fate Determinants Section, NINDS, NIH, Bethesda, Maryland, USA.
BMC Genomics. 2008 Aug 1;9:371. doi: 10.1186/1471-2164-9-371.
The presence of highly conserved sequences within cis-regulatory regions can serve as a valuable starting point for elucidating the basis of enhancer function. This study focuses on regulation of gene expression during the early events of Drosophila neural development. We describe the use of EvoPrinter and cis-Decoder, a suite of interrelated phylogenetic footprinting and alignment programs, to characterize highly conserved sequences that are shared among co-regulating enhancers.
Analysis of in vivo characterized enhancers that drive neural precursor gene expression has revealed that they contain clusters of highly conserved sequence blocks (CSBs) made up of shorter shared sequence elements which are present in different combinations and orientations within the different co-regulating enhancers; these elements contain either known consensus transcription factor binding sites or consist of novel sequences that have not been functionally characterized. The CSBs of co-regulated enhancers share a large number of sequence elements, suggesting that a diverse repertoire of transcription factors may interact in a highly combinatorial fashion to coordinately regulate gene expression. We have used information gained from our comparative analysis to discover an enhancer that directs expression of the nervy gene in neural precursor cells of the CNS and PNS.
The combined use EvoPrinter and cis-Decoder has yielded important insights into the combinatorial appearance of fundamental sequence elements required for neural enhancer function. Each of the 30 enhancers examined conformed to a pattern of highly conserved blocks of sequences containing shared constituent elements. These data establish a basis for further analysis and understanding of neural enhancer function.
顺式调控区域内高度保守序列的存在可作为阐明增强子功能基础的宝贵起点。本研究聚焦于果蝇神经发育早期事件中的基因表达调控。我们描述了使用EvoPrinter和顺式解码器（一套相互关联的系统发育足迹和比对程序）来表征共同调控增强子之间共享的高度保守序列。
对驱动神经前体基因表达的体内特征化增强子的分析表明，它们包含由较短共享序列元件组成的高度保守序列块（CSB）簇，这些元件以不同组合和方向存在于不同的共同调控增强子中；这些元件要么包含已知的共有转录因子结合位点，要么由尚未进行功能表征的新序列组成。共同调控增强子的CSB共享大量序列元件，这表明多种转录因子可能以高度组合的方式相互作用，以协调调控基因表达。我们利用从比较分析中获得的信息发现了一个增强子，它指导nervy基因在中枢神经系统和外周神经系统的神经前体细胞中表达。
EvoPrinter和顺式解码器的联合使用为深入了解神经增强子功能所需基本序列元件的组合出现提供了重要见解。所检测的30个增强子中的每一个都符合包含共享组成元件的高度保守序列块模式。这些数据为进一步分析和理解神经增强子功能奠定了基础。
