Conservation of transcription factor binding specificities across 600 million years of bilateria evolution.
Conservation of transcription factor binding specificities across 600 million years of bilateria evolution.
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DOI：
10.7554/elife.04837
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发表时间：
2015-03-17
期刊：
影响因子：
7.7
通讯作者：
Taipale J
中科院分区：
文献类型：
--
作者：
Nitta KR;Jolma A;Yin Y;Morgunova E;Kivioja T;Akhtar J;Hens K;Toivonen J;Deplancke B;Furlong EE;Taipale J
物种形态的差异主要归因于蛋白质组织特异性表达的遗传差异，这可以通过顺式调控元件的差异或通过改变转录因子（TF）的结合特异性来实现。后者的相对重要性一直难以评估，因为以前的TF结合特异性的系统分析已在不同物种中使用不同的方法进行。为了解决这个问题，我们确定了242果蝇TF的结合特异性，并将其与人类和小鼠的数据进行比较。该分析表明，TF结合特异性是高度保守的果蝇和哺乳动物之间，和orthopathic TF，相似性甚至延伸到非常微妙的二核苷酸结合偏好的水平。少数人TF不同的特异性功能的细胞类型中没有发现果蝇，表明TF特异性的演变有助于出现新类型的分化细胞。http://dx.doi.org/10.7554/eLife.04837.001苍蝇看起来与人类非常不同，但两者都是6亿多年前存在的共同祖先的后裔。动物物种之间的一些差异是由于它们具有不同的基因：包含制造蛋白质和其他分子的指令的DNA片段。然而，通常差异是由相同或相似的基因在不同时间和不同组织中打开和关闭引起的。控制基因何时何地表达的指令写在位于基因调控区的DNA碱基序列中。这些指令是用一种通常被称为“基因调控代码”的语言编写的。这种编码被称为转录因子的蛋白质读取和解释，这些转录因子与特定的DNA序列（或“DNA单词”）结合，并增加或减少基因表达。因此，物种之间基因表达的变化可能是由于转录因子的变化和/或特定基因调控区域内指令的变化。基因调控区在物种之间并不十分保守。然而，目前还不清楚这些区域中的指令是否使用相同的基因调控代码编写，以及不同物种中发现的转录因子是否识别不同的DNA单词。Nitta等人现在已经使用高通量方法来鉴定被称为黑腹果蝇的果蝇的242个转录因子识别的DNA单词。Nitta等人随后使用新的计算工具来寻找被每个转录因子识别的基序或DNA单词的集合。通过比较这些基序，他们观察到，尽管经过了6亿多年的进化，但在人类和小鼠中发现的几乎所有已知基序都能被果蝇转录因子识别。Nitta等人指出，果蝇和人类都有转录因子，可以识别一些独特的基序，并赋予每个物种特有的特性。例如，一些控制果蝇翅膀发育的转录因子在人类中并不存在。此外，果蝇既缺乏产生粘液的杯状细胞，也缺乏识别由控制人类这些细胞发育的转录因子读取的基序的能力。Nitta等人的发现还表明，转录因子不会进化到识别细微不同的DNA基序，而是似乎被限制识别相同的基序。因此，就像指导如何构建蛋白质的遗传密码一样，决定DNA序列如何指导基因表达的基因调控密码在动物中也高度保守。用于指导动物发展的语言，因此，数百万年来保持非常相似。使动物不同的是使用这种语言写入其基因调控区的指令的内容和长度的差异。DOI：http://dx.doi.org/10.7554/eLife.04837.002
Divergent morphology of species has largely been ascribed to genetic differences in the tissue-specific expression of proteins, which could be achieved by divergence in cis-regulatory elements or by altering the binding specificity of transcription factors (TFs). The relative importance of the latter has been difficult to assess, as previous systematic analyses of TF binding specificity have been performed using different methods in different species. To address this, we determined the binding specificities of 242 Drosophila TFs, and compared them to human and mouse data. This analysis revealed that TF binding specificities are highly conserved between Drosophila and mammals, and that for orthologous TFs, the similarity extends even to the level of very subtle dinucleotide binding preferences. The few human TFs with divergent specificities function in cell types not found in fruit flies, suggesting that evolution of TF specificities contributes to emergence of novel types of differentiated cells. DOI: http://dx.doi.org/10.7554/eLife.04837.001 Flies look very different from humans, but both are descended from a common ancestor that existed over 600 million years ago. Some differences between animal species are due to them having different genes: stretches of DNA that contain the instructions to make proteins and other molecules. However, often differences are caused by the same or similar genes being switched on and off at different times and in different tissues in each species. The instructions that control when and where a gene is expressed are written in the sequence of DNA bases located in the regulatory region of the gene. These instructions are written in a language that is often called the ‘gene regulatory code’. This code is read and interpreted by proteins called transcription factors that bind to specific sequences of DNA (or ‘DNA words’) and increase or decrease gene expression. Changes in gene expression between species could therefore be due to changes in the transcription factors and/or changes in the instructions within the regulatory regions of specific genes. Gene regulatory regions are not well conserved between species. However, it is unclear if the instructions in these regions are written using the same gene regulatory code, and whether transcription factors found in different species recognize different DNA words. Nitta et al. have now used high-throughput methods to identify the DNA words recognized by 242 transcription factors from a fruit fly called Drosophila melanogaster. Nitta et al. then used new computational tools to find motifs, or collections of DNA words, that are recognized by each of the transcription factors. By comparing the motifs, they observed that, in spite of more than 600 million years of evolution, almost all known motifs found in humans and mice were recognized by fruit fly transcription factors. Nitta et al. noted that both fruit flies and humans have transcription factors that recognize a few unique motifs, and confer properties that are specific to each species. For example, some of the transcription factors that control the development of the fruit fly wing are not present in humans. Moreover, fruit flies lack both mucus-producing goblet cells and the ability to recognize a motif read by the transcription factor that controls the development of these cells in humans. The findings of Nitta et al. also indicate that transcription factors do not evolve to recognize subtly different DNA motifs, but instead appear constrained to recognize the same motifs. Thus, much like the genetic code that instructs how to build proteins, the gene regulatory code that determines how DNA sequences direct gene expression is also highly conserved in animals. The language used to guide the development of animals has, as such, remained very similar for millions of years. What makes animals different is differences in the content and length of the instructions that are written using this language into the regulatory regions of their genes. DOI: http://dx.doi.org/10.7554/eLife.04837.002