Dependencies among editing sites in serotonin 2C receptor mRNA.
Dependencies among editing sites in serotonin 2C receptor mRNA.
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DOI：
10.1371/journal.pcbi.1002663
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发表时间：
2012
影响因子：
4.3
通讯作者：
Dracheva S
中科院分区：
文献类型：
--
作者：
Carmel L;Koonin EV;Dracheva S
5-羟色胺2C受体（5-HT 2CR）-不同神经过程的关键调节因子-表现出功能变异性，其来源于通过位点特异性腺苷脱氨基（A至I前mRNA编辑）在五个不同位点编辑其前mRNA。在这里，我们描述了一种统计技术，该技术是为了分析五个网站的编辑状态之间的依赖关系而开发的。通过比较多个个体中的编辑模式来估计所观察到的相关性的统计显著性。对于人和大鼠5-HT 2CR，发现物理上邻近的位点A和B的编辑状态是强烈依赖的。相反，在物理上也很接近的站点C和D的编辑状态似乎不是直接依赖的，而是分别通过对站点A和B的依赖性来链接的。我们观察到人类和大鼠的编辑模式之间存在明显差异：在人类中，位点A是其他位点编辑状态的关键决定因素，而在大鼠中，这一作用属于位点B。编辑位点之间的依赖性结构在大鼠中比在人类中明显更简单，这意味着5-HT 2CR编辑的调节更复杂，并且通过推断，在人脑中的功能也更复杂。因此，对5-HT 2CR编辑模式的详尽统计分析表明，位点A和B的编辑状态是其他三个位点的编辑状态的主要决定因素，因此是总体编辑模式的主要决定因素。综上所述，这些发现使我们能够提出ADAR 1和ADAR 2在5-HT 2CR编辑中协同作用的机制模型。这里开发的统计方法可以应用到其他情况下的相互依赖性的修饰位点之间的RNA和蛋白质。5-羟色胺受体2C是影响进食行为、睡眠、性行为、焦虑和抑郁的多种神经过程的关键调节因子。受体本身的功能通过所谓的前mRNA编辑来调节，即在五个不同位点中的位点特异性腺苷脱氨。5-羟色胺受体mRNA中编辑位点的数量越多，它编码的受体的活性就越低。在这里，我们使用人类和大鼠大脑的大规模平行测序结果来阐明五个位点的编辑状态之间的依赖关系。尽管这个问题看起来很简单，但消除这些依赖关系的歧义是一项艰巨的任务，需要开发一种新的统计技术。我们采用这种方法来分析在受体mRNA的5个敏感位点中编辑之间的依赖性，并发现邻近的并列位点A和B是强烈相互依赖的，并且这两个位点的编辑状态是其他三个位点的编辑状态的主要决定因素，因此是整体编辑模式的主要决定因素。我们开发的用于分析mRNA编辑的统计方法可以应用于RNA和蛋白质中多位点修饰的其他情况。
The serotonin 2C receptor (5-HT2CR)–a key regulator of diverse neurological processes–exhibits functional variability derived from editing of its pre-mRNA by site-specific adenosine deamination (A-to-I pre-mRNA editing) in five distinct sites. Here we describe a statistical technique that was developed for analysis of the dependencies among the editing states of the five sites. The statistical significance of the observed correlations was estimated by comparing editing patterns in multiple individuals. For both human and rat 5-HT2CR, the editing states of the physically proximal sites A and B were found to be strongly dependent. In contrast, the editing states of sites C and D, which are also physically close, seem not to be directly dependent but instead are linked through the dependencies on sites A and B, respectively. We observed pronounced differences between the editing patterns in humans and rats: in humans site A is the key determinant of the editing state of the other sites, whereas in rats this role belongs to site B. The structure of the dependencies among the editing sites is notably simpler in rats than it is in humans implying more complex regulation of 5-HT2CR editing and, by inference, function in the human brain. Thus, exhaustive statistical analysis of the 5-HT2CR editing patterns indicates that the editing state of sites A and B is the primary determinant of the editing states of the other three sites, and hence the overall editing pattern. Taken together, these findings allow us to propose a mechanistic model of concerted action of ADAR1 and ADAR2 in 5-HT2CR editing. Statistical approach developed here can be applied to other cases of interdependencies among modification sites in RNA and proteins. The serotonin receptor 2C is a key regulator of diverse neurological processes that affect feeding behavior, sleep, sexual behavior, anxiety and depression. The function of the receptor itself is regulated via so-called pre-mRNA editing, i.e. site-specific adenosine deamination in five distinct sites. The greater the number of edited sites in the serotonin receptor mRNA, the lower the activity of the receptor it encodes. Here we used the results of extensive massively parallel sequencing from human and rat brains to elucidate the dependencies among the editing states of the five sites. Despite the apparent simplicity of the problem, disambiguation of these dependencies is a difficult task that required development of a new statistical technique. We employed this method to analyse the dependencies among editing in the 5 susceptible sites of the receptor mRNA and found that the proximal, juxtaposed sites A and B are strongly interdependent, and that the editing state of these two sites is a major determinant of the editing states of the other three sites, and hence the overall editing pattern. The statistical approach we developed for the analysis of mRNA editing can be applied to other cases of multiple site modification in RNA and proteins.
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