Regulatory circuit of human microRNA biogenesis.
Regulatory circuit of human microRNA biogenesis.
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DOI：
10.1371/journal.pcbi.0030067
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发表时间：
2007-04-20
影响因子：
4.3
通讯作者：
John B
中科院分区：
文献类型：
--
作者：
Lee J;Li Z;Brower-Sinning R;John B
miRNAs（microRNAs）是一类内源性小RNA，被认为负调节蛋白质的产生。许多miRNAs的异常表达与癌症和其他疾病有关。关于调节miRNAs表达的因子知之甚少。我们已经确定了许多调控元件上游的miRNA基因可能是必不可少的转录和转录后调控的miRNA。新发现的调控基序频繁出现，并在miRNA上游的多个拷贝中。与miRNA上游序列的核苷酸组成相比，基序高度富集G和C核苷酸。尽管使用miRNA上游序列预测了这些基序，但我们发现99%的最高预测基序优先发生在蛋白质编码基因转录起始位点上游的前500个核苷酸内;观察到的位置偏好强调了本研究中确定的基序的有效性和重要性。我们的研究还提出了一种可能性，即蛋白质编码基因的大量特征良好的疾病相关转录因子（TF）有助于癌症等疾病中的异常miRNA表达。对预测的miRNA-蛋白质相互作用的进一步分析使我们假设包括c-Myb、NF-Y、Sp-1、MTF-1和AP-2α在内的TF是miRNA表达的主调节因子。我们的预测是一个坚实的起点，为系统阐明的病因基础异常表达模式的疾病相关的（例如，癌症）miRNAs。因此，我们指出，对调节miRNA的TF的集中研究将在开发miRNA相关疾病的治疗方法中至关重要。通过一种新的计算方法K-因子来促进miRNA调控基序的鉴定。K因子预测一组功能相关序列中的调控基序，而不依赖于进化保守性。microRNA（miRNAs）是一种非常小的RNA，被认为控制细胞中蛋白质的产生。最近的研究将miRNAs与几种类型的癌症联系起来。一些研究强烈表明，miRNA可用作各种癌症的诊断和预后标志物。因此，尽管miRNAs似乎已经在癌症生物学中开辟了新的篇章，但关于为什么miRNAs与癌症等疾病密切相关的基本问题仍然不清楚。在这里，我们致力于系统地确定调节miRNA生物合成的因素。我们首先确定了大量的DNA序列元素，是miRNA基因的特征，使用一种新的计算方法命名为K因子。然后使用序列元件来匹配已知的蛋白质结合位点，以鉴定调节miRNA生物发生的特定蛋白质（转录因子（TF））。基于我们的观察，我们提出了一个假设，即一些已知的TF是主要负责在癌症和其他疾病中的miRNA的异常调节。
miRNAs (microRNAs) are a class of endogenous small RNAs that are thought to negatively regulate protein production. Aberrant expression of many miRNAs is linked to cancer and other diseases. Little is known about the factors that regulate the expression of miRNAs. We have identified numerous regulatory elements upstream of miRNA genes that are likely to be essential to the transcriptional and posttranscriptional regulation of miRNAs. Newly identified regulatory motifs occur frequently and in multiple copies upstream of miRNAs. The motifs are highly enriched in G and C nucleotides, in comparison with the nucleotide composition of miRNA upstream sequences. Although the motifs were predicted using sequences that are upstream of miRNAs, we find that 99% of the top-predicted motifs preferentially occur within the first 500 nucleotides upstream of the transcription start sites of protein-coding genes; the observed preference in location underscores the validity and importance of the motifs identified in this study. Our study also raises the possibility that a considerable number of well-characterized, disease-associated transcription factors (TFs) of protein-coding genes contribute to the abnormal miRNA expression in diseases such as cancer. Further analysis of predicted miRNA–protein interactions lead us to hypothesize that TFs that include c-Myb, NF-Y, Sp-1, MTF-1, and AP-2α are master-regulators of miRNA expression. Our predictions are a solid starting point for the systematic elucidation of the causative basis for aberrant expression patterns of disease-related (e.g., cancer) miRNAs. Thus, we point out that focused studies of the TFs that regulate miRNAs will be paramount in developing cures for miRNA-related diseases. The identification of the miRNA regulatory motifs was facilitated by a new computational method, K-Factor. K-Factor predicts regulatory motifs in a set of functionally related sequences, without relying on evolutionary conservation. microRNAs (miRNAs) are unusually small RNAs that are thought to control the production of proteins in the cell. Recent studies have linked miRNAs to several types of cancers. Several studies strongly suggest that miRNAs could be useful as diagnostic and prognostic markers of various cancers. Thus, although miRNAs appear to have opened up a new chapter in cancer biology, the fundamental question regarding why miRNAs are strongly associated with diseases such as cancer remain unclear. Here, we endeavored to systematically identify the factors that regulate miRNA biogenesis. We first identified a large number of DNA sequence elements that are characteristic of miRNA genes, using a new computational method named K-Factor. The sequence elements were then used to match known protein binding sites to identify specific proteins (transcription factors (TF)) that regulate miRNA biogenesis. Based on our observations, we put forward the hypothesis that a number of known TFs are primarily responsible for the aberrant regulation of miRNAs in cancer and other diseases.
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