Kircher Martin, Bock Christoph, Paulsen Martina
Max-Planck-Institut für Informatik, Saarbrücken, Germany.
BMC Genomics. 2008 Jul 23;9:346. doi: 10.1186/1471-2164-9-346.
MicroRNAs play an important functional role in post-transcriptional gene regulation. One of the largest known microRNA clusters is located within the imprinted Dlk1/Gtl2 region on human chromosome 14 and mouse chromosome 12. This cluster contains more than 40 microRNA genes that are expressed only from the maternal chromosome in mouse.
To shed light on the function of these microRNAs and possible crosstalk between microRNA-based gene regulation and genomic imprinting, we performed extensive in silico analyses of the microRNAs in this imprinted region and their predicted target genes.Bioinformatic analysis reveals that these microRNAs are highly conserved in both human and mouse. Whereas the microRNA precursors at this locus mostly belong to large sequence families, the mature microRNAs sequences are highly divergent. We developed a target gene prediction approach that combines three widely used prediction methods and achieved a sufficiently high prediction accuracy. Target gene sets predicted for individual microRNAs derived from the imprinted region show little overlap and do not differ significantly in their properties from target genes predicted for a group of randomly selected microRNAs. The target genes are enriched with long and GC-rich 3' UTR sequences and are preferentially annotated to development, regulation processes and cell communication. Furthermore, among all analyzed human and mouse genes, the predicted target genes are characterized by consistently higher expression levels in all tissues considered.
Our results suggest a complex evolutionary history for microRNA genes in this imprinted region, including an amplification of microRNA precursors in a mammalian ancestor, and a rapid subsequent divergence of the mature sequences. This produced a broad spectrum of target genes. Further, our analyses did not uncover a functional relation between imprinted gene regulation of this microRNA-encoding region, expression patterns or functions of predicted target genes. Specifically, our results indicate that these microRNAs do not regulate a particular set of genes. We conclude that these imprinted microRNAs do not regulate a particular set of genes. Rather, they seem to stabilize expression of a variety of genes, thereby being an integral part of the genome-wide microRNA gene regulatory network.
微小RNA在转录后基因调控中发挥着重要的功能作用。已知最大的微小RNA簇之一位于人类14号染色体和小鼠12号染色体上的印记Dlk1/Gtl2区域内。该簇包含40多个微小RNA基因，在小鼠中仅从母本染色体表达。
为了阐明这些微小RNA的功能以及基于微小RNA的基因调控与基因组印记之间可能存在的相互作用，我们对这个印记区域中的微小RNA及其预测的靶基因进行了广泛的计算机分析。生物信息学分析表明，这些微小RNA在人类和小鼠中都高度保守。虽然该位点的微小RNA前体大多属于大的序列家族，但成熟的微小RNA序列差异很大。我们开发了一种结合三种广泛使用的预测方法的靶基因预测方法，并取得了足够高的预测准确率。从印记区域衍生的单个微小RNA预测的靶基因集几乎没有重叠，并且在性质上与一组随机选择的微小RNA预测的靶基因没有显著差异。靶基因富含长的和富含GC的3'UTR序列，并且优先注释到发育、调控过程和细胞通讯。此外，在所有分析的人类和小鼠基因中，预测的靶基因在所有考虑的组织中都具有始终较高的表达水平。
我们的结果表明，这个印记区域中的微小RNA基因具有复杂的进化历史，包括在哺乳动物祖先中微小RNA前体的扩增，以及随后成熟序列的快速分化。这产生了广泛的靶基因。此外，我们的分析没有发现这个编码微小RNA区域的印记基因调控、预测靶基因的表达模式或功能之间的功能关系。具体而言，我们的结果表明这些微小RNA并不调控特定的一组基因。我们得出结论，这些印记微小RNA并不调控特定的一组基因。相反，它们似乎稳定了多种基因的表达，从而成为全基因组微小RNA基因调控网络的一个组成部分。
