Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation.
Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation.
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DOI：
10.1371/journal.pgen.1000106
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发表时间：
2008-06-27
期刊：
影响因子：
4.5
通讯作者：
Eisen, Michael B.
中科院分区：
文献类型：
--
作者：
Hare, Emily E.;Peterson, Brant K.;Iyer, Venky N.;Meier, Rudolf;Eisen, Michael B.
由动物调控序列指定的基因表达模式通常被认为是由其包含的转录因子结合位点的特殊排列引起的。然而，我们在这里证明，结合位点几乎完全重排的调控序列仍然可以产生相同的输出。我们对6种食腐蝇（Sepsidae）的连跳过位点进行了测序，这些食腐蝇与模式物种黑腹果蝇（Drosophila melanogaster）高度分化，但却共享其发育基因表达的基本模式。尽管在sepsid eve增强子和果蝇的同类基因之间几乎没有序列相似性，但sepsid和果蝇增强子在转基因果蝇胚胎中驱动几乎相同的表达模式。我们得出的结论是，连接调控序列和转录装置的分子机制比以前认识到的更灵活。在探索这些不同的序列以确定其相似功能的共同特征时，我们发现了少数短（20-30 bp）序列在物种中几乎完全保守。这些高度保守的序列对重叠或相邻的结合位点非常丰富。总之，这些观察结果表明，结合位点之间的局部排列比它们在顺式调节功能的更大单元中的整体排列更重要。受精卵向复杂的多细胞生物的转变是一个精心编排的过程，在这个过程中，数千个基因在特定的空间和时间模式下开启和关闭，赋予新生细胞和组织独特的物理特性和行为。为了了解生物体的基因组如何指定其形式和功能，因此有必要了解基因表达模式如何在DNA中编码。对黑腹果蝇（Drosophila melanogaster）几十年的分析已经确定了许多调节序列，但还没有完全阐明它们是如何工作的。在这里，我们利用自然选择的记录来探索这些序列的功能。我们从1亿多年前从果蝇分化出来的食腐蝇物种中鉴定出了调控序列。虽然这些调控序列与果蝇的调控序列几乎完全不同，但它们在果蝇胚胎中驱动相同的表达模式，显示了解释调控DNA的分子机器的极端灵活性。然而，这些序列产生的相同输出意味着它们必须有一些共同之处，我们描述了从这些比较中出现的调控序列组织和功能的一个共同特征。我们的方法可以推广到任何调控系统和物种，我们相信，越来越多的序列不同但输出相似的调控序列将揭示基因调控的分子逻辑。
The gene expression pattern specified by an animal regulatory sequence is generally viewed as arising from the particular arrangement of transcription factor binding sites it contains. However, we demonstrate here that regulatory sequences whose binding sites have been almost completely rearranged can still produce identical outputs. We sequenced the even-skipped locus from six species of scavenger flies (Sepsidae) that are highly diverged from the model species Drosophila melanogaster, but share its basic patterns of developmental gene expression. Although there is little sequence similarity between the sepsid eve enhancers and their well-characterized D. melanogaster counterparts, the sepsid and Drosophila enhancers drive nearly identical expression patterns in transgenic D. melanogaster embryos. We conclude that the molecular machinery that connects regulatory sequences to the transcription apparatus is more flexible than previously appreciated. In exploring this diverse collection of sequences to identify the shared features that account for their similar functions, we found a small number of short (20–30 bp) sequences nearly perfectly conserved among the species. These highly conserved sequences are strongly enriched for pairs of overlapping or adjacent binding sites. Together, these observations suggest that the local arrangement of binding sites relative to each other is more important than their overall arrangement into larger units of cis-regulatory function. The transformation of a fertilized egg into a complex, multicellular organism is a carefully choreographed process in which thousands of genes are turned on and off in specific spatial and temporal patterns that confer distinct physical properties and behaviors on emerging cells and tissues. To understand how an organism's genome specifies its form and function, it is therefore necessary to understand how patterns of gene expression are encoded in DNA. Decades of analysis of the fruit fly Drosophila melanogaster have identified numerous regulatory sequences, but have not fully illuminated how they work. Here we harness the record of natural selection to probe the function of these sequences. We identified regulatory sequences from scavenger fly species that diverged from Drosophila over 100 million years ago. While these regulatory sequences are almost completely different from their Drosophila counterparts, they drive identical expression patterns in Drosophila embryos, demonstrating extreme flexibility in the molecular machines that interpret regulatory DNA. Yet, the identical outputs produced by these sequences mean they must have something in common, and we describe one shared feature of regulatory sequence organization and function that has emerged from these comparisons. Our approach can be generalized to any regulatory system and species, and we believe that a growing collection of regulatory sequences with dissimilar sequences but similar outputs will reveal the molecular logic of gene regulation.
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影响因子：
64.8
作者：
Clark, Andrew G.;Eisen, Michael B.;MacCallum, Iain
通讯作者：
MacCallum, Iain
影响因子：
12.3
作者：
Berman BP;Pfeiffer BD;Laverty TR;Salzberg SL;Rubin GM;Eisen MB;Celniker SE
通讯作者：
Celniker SE
DOI：
10.1073/pnas.231608898
发表时间：
2002-01-22
影响因子：
11.1
作者：
Berman, BP;Nibu, Y;Eisen, MB
通讯作者：
Eisen, MB
影响因子：
11.4
作者：
Arnosti, DN;Gray, S;Levine, M
通讯作者：
Levine, M
影响因子：
64.8
作者：
Clyde, DE;Corado, MSG;Small, S
通讯作者：
Small, S