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A novel microRNA and transcription factor mediated regulatory network in schizophrenia.

ABSTRACT: Schizophrenia is a complex brain disorder with molecular mechanisms that have yet to be elucidated. Previous studies have suggested that changes in gene expression may play an important role in the etiology of schizophrenia, and that microRNAs (miRNAs) and transcription factors (TFs) are primary regulators of this gene expression. So far, several miRNA-TF mediated regulatory modules have been verified. We hypothesized that miRNAs and TFs might play combinatory regulatory roles for schizophrenia genes and, thus, explored miRNA-TF regulatory networks in schizophrenia.We identified 32 feed-forward loops (FFLs) among our compiled schizophrenia-related miRNAs, TFs and genes. Our evaluation revealed that these observed FFLs were significantly enriched in schizophrenia genes. By converging the FFLs and mutual feedback loops, we constructed a novel miRNA-TF regulatory network for schizophrenia. Our analysis revealed EGR3 and hsa-miR-195 were core regulators in this regulatory network. We next proposed a model highlighting EGR3 and miRNAs involved in signaling pathways and regulatory networks in the nervous system. Finally, we suggested several single nucleotide polymorphisms (SNPs) located on miRNAs, their target sites, and TFBSs, which may have an effect in schizophrenia gene regulation.This study provides many insights on the regulatory mechanisms of genes involved in schizophrenia. It represents the first investigation of a miRNA-TF regulatory network for a complex disease, as demonstrated in schizophrenia.

SUBMITTER: Guo AY

PROVIDER: S-EPMC2834616 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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A novel microRNA and transcription factor mediated regulatory network in schizophrenia.

Guo An-Yuan AY Sun Jingchun J Jia Peilin P Zhao Zhongming Z

BMC systems biology 20100215

<h4>Background</h4>Schizophrenia is a complex brain disorder with molecular mechanisms that have yet to be elucidated. Previous studies have suggested that changes in gene expression may play an important role in the etiology of schizophrenia, and that microRNAs (miRNAs) and transcription factors (TFs) are primary regulators of this gene expression. So far, several miRNA-TF mediated regulatory modules have been verified. We hypothesized that miRNAs and TFs might play combinatory regulatory roles ...[more]

PMID: 20156358

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Project description:BackgroundMicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.ResultsWe constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.ConclusionThe genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.

Project description:Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.

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A novel microRNA and transcription factor mediated regulatory network in schizophrenia.

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A novel microRNA and transcription factor mediated regulatory network in schizophrenia.

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