Quantitative insights into stochastic monoallelic expression of cytokine genes
Quantitative insights into stochastic monoallelic expression of cytokine genes
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DOI：
10.1038/sj.icb.7100057
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发表时间：
2007-06-01
影响因子：
4
通讯作者：
Carneiro, Jorge
中科院分区：
文献类型：
--
作者：
Paixao, Tiago;Carvalho, Tiago P.;Carneiro, Jorge
来自两个亲本等位基因的基因表达通过掩盖有害的隐性突变的影响和通过减少二倍体生物体中基因表达的噪音而有益。然而，一类基因优先或严格地从单个等位基因表达。避免双等位基因表达的选择性优势对于等位基因排除的抗原受体和气味受体基因、在女性中经历X染色体失活的基因和亲本基因组印记基因是清楚的。相比之下，免疫系统中细胞因子基因的主要和随机单等位基因表达没有明确的生物学原理，并且潜在的机制是难以捉摸和有争议的。阐明主要单等位基因表达的机制将有助于更好地理解其最终的生物学功能。这促使了一个定量框架的发展，可以描述IL-10基因的等位基因表达模式的动态，从中可以获得一般的定量见解。我们报告说，这些模式的等位基因表达的实验观察不能很容易地调和与一个简单的模型随机转录激活，其中两个等位基因，在任何时候，同样胜任转录。相反，这些观察呼吁采取行动的真核转录调控的一般模型，根据该基因座的转录能力是动态的，涉及多个，合作和随机的修改步骤。在这个模型中，等位基因变得转录活跃的概率是它积累的染色质修饰数量的函数。该模型的属性的基础上，我们认为，占主导地位的单等位基因表达可能没有适应性的作用，并可能在间接选择低频率的表达细胞。
Gene expression from both parental alleles is beneficial by masking the effects of deleterious recessive mutations and by reducing the noise in gene expression in diploid organisms. However, a class of genes are expressed preferentially or strictly from a single allele. The selective advantage of avoiding biallelic expression is clear for allelic-excluded antigen receptor and odorant receptor genes, genes undergoing X-chromosome inactivation in females and parental genomic imprinted genes. In contrast, there is no clear biological rationale for the predominant and stochastic monoallelic expression of cytokine genes in the immune system, and the underlying mechanism is elusive and controversial. A clarification of the mechanism of predominant monoallelic expression would be instrumental in better understanding its eventual biological functional. This prompted the development of a quantitative framework that could describe the dynamics of the pattern of allele expression of the IL-10 gene, from which general quantitative insights could be gained. We report that the experimental observations on these patterns of allelic expression cannot be easily reconciled with a simple model of stochastic transcriptional activation, in which the two alleles are, at any time, equally competent for transcription. Instead, these observations call into action a general model of eukaryotic transcriptional regulation according to which the locus competence for transcription is dynamic, involving multiple, cooperative and stochastic modification steps. In this model, the probability that an allele becomes transcriptionally active is a function of the number of chromatin modifications that it accumulated. On the basis of the properties of this model, we argue that predominant monoallelic expression might have had no adaptive role, and may have evolved under indirect selection for low frequency of expressing cells.