Dataset Information

Identification of a two-layer regulatory network of proliferation-related microRNAs in hepatoma cells.

ABSTRACT: To elucidate how microRNA (miRNA)-regulated networks contribute to the uncontrolled growth of hepatoma cells (HCCs), we identified several proliferation-related miRNAs by comparing miRNA expression patterns in clinical HCC samples and growth-arrested HepG2 cells. To explore the molecular functions targeted by these miRNAs, we classified genes differentially expressed in clinical HCC samples into six functional clusters based on their functional similarity. Using target enrichment analysis, we discovered that targets of three proliferation-related miRNAs-miR-101, miR-199a-3p and miR-139-5p-were significantly enriched in the 'transcription regulation' functional cluster. An interactome network consisting of these three miRNAs and genes in the 'transcriptional control' cluster revealed that all three miRNAs were highly connected hubs in the network. All three miRNA-centered subnetworks displayed characteristics of a two-layer regulatory architecture, with transcription factors and epigenetic modulators as the first neighbors and genes involved in cell-cycle progression as second neighbors. The overexpression of miR-101 in HepG2 cells reduced the expression of transcription regulators and genes in cell-cycle progression and suppressed the proliferation and colony formation of HepG2 cells. This study not only provides direct experimental data to support the 'miRNA-centered two-layer regulatory network' model, but our results also suggest that such a combinatorial network model may be widely used by miRNAs to regulate critical biological processes.

SUBMITTER: Huang Y

PROVIDER: S-EPMC3488236 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Identification of a two-layer regulatory network of proliferation-related microRNAs in hepatoma cells.

Huang Yi Y Chen Hua-Chien HC Chiang Chao-Wei CW Yeh Chau-Ting CT Chen Shu-Jen SJ Chou Chen-Kung CK

Nucleic acids research 20120825 20

To elucidate how microRNA (miRNA)-regulated networks contribute to the uncontrolled growth of hepatoma cells (HCCs), we identified several proliferation-related miRNAs by comparing miRNA expression patterns in clinical HCC samples and growth-arrested HepG2 cells. To explore the molecular functions targeted by these miRNAs, we classified genes differentially expressed in clinical HCC samples into six functional clusters based on their functional similarity. Using target enrichment analysis, we di ...[more]

PMID: 22923518

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Project description:BackgroundSarcopenia is highly prevalent in elderly individuals and has a significant adverse effect on their physical health and quality of life, but the mechanisms remain unclear. Studies have indicated that transcription factors (TFs) and the immune microenvironment play a vital role in skeletal muscle atrophy.MethodsRNA-seq data of 40 muscle samples were downloaded from the GEO database. Then, differentially expressed genes (DEGs), TFs(DETFs), pathways(DEPs), and the expression of immune gene sets were identified with limma, edgeR, GO, KEGG, ORA, GSVA, and ssGSEA. Furthermore, the results above were integrated into coexpression analysis by Pearson correlation analysis (PCA). Significant coexpression patterns were used to construct the immune-related transcriptional regulatory network by Cytoscape and potential medicine targeting the network was screened by Connectivity Map. Finally, the regulatory mechanisms and RNA expression of DEGs and DETFs were identified by multiple online databases and RT‒qPCR.ResultsWe screened 808 DEGs (log2 fold change (FC) > 1 or < - 1, p < 0.05), 4 DETFs (log2FC > 0.7 or < - 0.7, p < 0.05), 304 DEPs (enrichment scores (ES) > 1 or < - 1, p < 0.05), and 1208 differentially expressed immune genes sets (DEIGSs) (p < 0.01). Based on the results of PCA (correlation coefficient (CC) > 0.4 or < - 0.4, p < 0.01), we then structured an immune-related network with 4 DETFs, 9 final DEGs, 11 final DEPs, and 6 final DEIGSs. Combining the results of online databases and in vitro experiments, we found that PAX5-SERPINA5-PI3K/Akt (CC ≤ 0.444, p ≤ 0.004) was a potential transcriptional regulation axis, and B cells (R = 0.437, p = 0.005) may play a vital role in this signal transduction. Finally, the compound of trichostatin A (enrichment = -0.365, specificity = 0.4257, p < 0.0001) might be a potential medicine for sarcopenia based on the PubChem database and the result of the literature review.ConclusionsWe first identified immune-related transcriptional regulatory network with high-throughput RNA-seq data in sarcopenia. We hypothesized that PAX5-SERPIAN5-PI3K/Akt axis is a potential mechanism in sarcopenia and that B cells may play a vital role in this signal transduction. In addition, trichostatin A might be a potential medicine for sarcopenia.

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.

Dataset Information

Identification of a two-layer regulatory network of proliferation-related microRNAs in hepatoma cells.

Publications

Identification of a two-layer regulatory network of proliferation-related microRNAs in hepatoma cells.

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