Dataset Information

MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features.

ABSTRACT: Synergistic regulations among multiple microRNAs (miRNAs) are important to understand the mechanisms of complex post-transcriptional regulations in humans. Complex diseases are affected by several miRNAs rather than a single miRNA. So, it is a challenge to identify miRNA synergism and thereby further determine miRNA functions at a system-wide level and investigate disease miRNA features in the miRNA-miRNA synergistic network from a new view. Here, we constructed a miRNA-miRNA functional synergistic network (MFSN) via co-regulating functional modules that have three features: common targets of corresponding miRNA pairs, enriched in the same gene ontology category and close proximity in the protein interaction network. Predicted miRNA synergism is validated by significantly high co-expression of functional modules and significantly negative regulation to functional modules. We found that the MFSN exhibits a scale free, small world and modular architecture. Furthermore, the topological features of disease miRNAs in the MFSN are distinct from non-disease miRNAs. They have more synergism, indicating their higher complexity of functions and are the global central cores of the MFSN. In addition, miRNAs associated with the same disease are close to each other. The structure of the MFSN and the features of disease miRNAs are validated to be robust using different miRNA target data sets.

SUBMITTER: Xu J

PROVIDER: S-EPMC3035454 | biostudies-other | 2011 Feb

REPOSITORIES: biostudies-other

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MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features.

Xu Juan J Li Chuan-Xing CX Li Yong-Sheng YS Lv Jun-Ying JY Ma Ye Y Shao Ting-Ting TT Xu Liang-De LD Wang Ying-Ying YY Du Lei L Zhang Yun-Peng YP Jiang Wei W Li Chun-Quan CQ Xiao Yun Y Li Xia X

Nucleic acids research 20101006 3

Synergistic regulations among multiple microRNAs (miRNAs) are important to understand the mechanisms of complex post-transcriptional regulations in humans. Complex diseases are affected by several miRNAs rather than a single miRNA. So, it is a challenge to identify miRNA synergism and thereby further determine miRNA functions at a system-wide level and investigate disease miRNA features in the miRNA-miRNA synergistic network from a new view. Here, we constructed a miRNA-miRNA functional synergis ...[more]

PMID: 20929877

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Project description:BackgroundAcidity is a major contributor to fruit quality. Several organic acids are present in apple fruit, but malic acid is predominant and determines fruit acidity. The trait is largely controlled by the Malic acid (Ma) locus, underpinning which Ma1 that putatively encodes a vacuolar aluminum-activated malate transporter1 (ALMT1)-like protein is a strong candidate gene. We hypothesize that fruit acidity is governed by a gene network in which Ma1 is key member. The goal of this study is to identify the gene network and the potential mechanisms through which the network operates.ResultsGuided by Ma1, we analyzed the transcriptomes of mature fruit of contrasting acidity from six apple accessions of genotype Ma_ (MaMa or Mama) and four of mama using RNA-seq and identified 1301 fruit acidity associated genes, among which 18 were most significant acidity genes (MSAGs). Network inferring using weighted gene co-expression network analysis (WGCNA) revealed five co-expression gene network modules of significant (P < 0.001) correlation with malate. Of these, the Ma1 containing module (Turquoise) of 336 genes showed the highest correlation (0.79). We also identified 12 intramodular hub genes from each of the five modules and 18 enriched gene ontology (GO) terms and MapMan sub-bines, including two GO terms (GO:0015979 and GO:0009765) and two MapMap sub-bins (1.3.4 and 1.1.1.1) related to photosynthesis in module Turquoise. Using Lemon-Tree algorithms, we identified 12 regulator genes of probabilistic scores 35.5-81.0, including MDP0000525602 (a LLR receptor kinase), MDP0000319170 (an IQD2-like CaM binding protein) and MDP0000190273 (an EIN3-like transcription factor) of greater interest for being one of the 18 MSAGs or one of the 12 intramodular hub genes in Turquoise, and/or a regulator to the cluster containing Ma1.ConclusionsThe most relevant finding of this study is the identification of the MSAGs, intramodular hub genes, enriched photosynthesis related processes, and regulator genes in a WGCNA module Turquoise that not only encompasses Ma1 but also shows the highest modular correlation with acidity. Overall, this study provides important insight into the Ma1-mediated gene network controlling acidity in mature apple fruit of diverse genetic background.

Project description:Co-expression network analyses provide insights into the molecular interactions underlying complex traits and diseases. In this study, co-expression network analysis was performed to detect expression patterns (modules or clusters) of microRNAs (miRNAs) during lactation, and to identify miRNA regulatory mechanisms for milk yield and component traits (fat, protein, somatic cell count (SCC), lactose, and milk urea nitrogen (MUN)) via miRNA target gene enrichment analysis. miRNA expression (713 miRNAs), and milk yield and components (Fat%, Protein%, lactose, SCC, MUN) data of nine cows at each of six different time points (day 30 (D30), D70, D130, D170, D230 and D290) of an entire lactation curve were used. Four modules or clusters (GREEN, BLUE, RED and TURQUOISE) of miRNAs were identified as important for milk yield and component traits. The GREEN and BLUE modules were significantly correlated (|r| > 0.5) with milk yield and lactose, respectively. The RED and TURQUOISE modules were significantly correlated (|r| > 0.5) with both SCC and lactose. In the GREEN module, three abundantly expressed miRNAs (miR-148a, miR-186 and miR-200a) were most significantly correlated to milk yield, and are probably the most important miRNAs for this trait. DDR1 and DDHX1 are hub genes for miRNA regulatory networks controlling milk yield, while HHEX is an important transcription regulator for these networks. miR-18a, miR-221/222 cluster, and transcription factors HOXA7, and NOTCH 3 and 4, are important for the regulation of lactose. miR-142, miR-146a, and miR-EIA17-14144 (a novel miRNA), and transcription factors in the SMAD family and MYB, are important for the regulation of SCC. Important signaling pathways enriched for target genes of miRNAs of significant modules, included protein kinase A and PTEN signaling for milk yield, eNOS and Noth signaling for lactose, and TGF ?, HIPPO, Wnt/?-catenin and cell cycle signaling for SCC. Relevant enriched gene ontology (GO)-terms related to milk and mammary gland traits included cell differentiation, G-protein coupled receptor activity, and intracellular signaling transduction. Overall, this study uncovered regulatory networks in which miRNAs interacted with each other to regulate lactation traits.

Project description:MicroRNAs (miRNA) regulate mRNA networks to coordinate cellular functions. In this study, we constructed gene co-expression networks to detect miRNA modules (clusters of miRNAs with similar expression patterns) and miRNA?mRNA pairs associated with blood (triacylglyceride and nonesterified fatty acids) and milk (milk yield, fat, protein, and lactose) components and milk fatty acid traits following dietary supplementation of cows' diets with 5% linseed oil (LSO) (n = 6 cows) or 5% safflower oil (SFO) (n = 6 cows) for 28 days. Using miRNA transcriptome data from mammary tissues of cows for co-expression network analysis, we identified three consensus modules: blue, brown, and turquoise, composed of 70, 34, and 86 miRNA members, respectively. The hub miRNAs (miRNAs with the most connections with other miRNAs) were miR-30d, miR-484 and miR-16b for blue, brown, and turquoise modules, respectively. Cell cycle arrest, and p53 signaling and transforming growth factor?beta (TGF-?) signaling pathways were the common gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched for target genes of the three modules. Protein percent (p = 0.03) correlated with the turquoise module in LSO treatment while protein yield (p = 0.003) and milk yield (p = 7 × 10-04) correlated with the turquoise model, protein and milk yields and lactose percent (p < 0.05) correlated with the blue module and fat percent (p = 0.04) correlated with the brown module in SFO treatment. Several fatty acids correlated (p < 0.05) with the blue (CLA:9,11) and brown (C4:0, C12:0, C22:0, C18:1n9c and CLA:10,12) modules in LSO treatment and with the turquoise (C14:0, C18:3n3 and CLA:9,11), blue (C14:0 and C23:0) and brown (C6:0, C16:0, C22:0, C22:6n3 and CLA:10,12) modules in SFO treatment. Correlation of miRNA and mRNA data from the same animals identified the following miRNA?mRNA pairs: miR-183/RHBDD2 (p = 0.003), miR-484/EIF1AD (p = 0.011) and miR-130a/SBSPON (p = 0.004) with lowest p-values for the blue, brown, and turquoise modules, respectively. Milk yield, protein yield, and protein percentage correlated (p < 0.05) with 28, 31 and 5 miRNA?mRNA pairs, respectively. Our results suggest that, the blue, brown, and turquoise modules miRNAs, hub miRNAs, miRNA?mRNA networks, cell cycle arrest GO term, p53 signaling and TGF-? signaling pathways have considerable influence on milk and blood phenotypes following dietary supplementation of dairy cows' diets with 5% LSO or 5% SFO.

Project description:BackgroundDespite advances in the understanding of neoplasm, patients with cervical cancer still have a poor prognosis. Identifying prognostic markers of cervical cancer may enable early detection of recurrence and more effective treatment.MethodsGene expression profiling data were acquired from the Gene Expression Omnibus database. After data normalization, genes with large variation were screened out. Next, we built co-expression modules by using weighted gene co-expression network analysis to investigate the relationship between the modules and clinical traits related to cervical cancer progression. Functional enrichment analysis was also applied on these co-expressed genes. We integrated the genes into a human protein-protein interaction (PPI) network to expand seed genes and build a co-expression network. For further analysis of the dataset, the Cancer Genome Atlas (TCGA) database was used to identify seed genes and their correlation to cervical cancer prognosis. Verification was further conducted by qPCR and the Human Protein Atlas (HPA) database to measure the expression of hub genes.ResultsUsing WGCNA, we identified 25 co-expression modules from 10,016 genes in 128 human cervical cancer samples. After functional enrichment analysis, the magenta, brown, and darkred modules were selected as the three most correlated modules for cancer progression. Additionally, seed genes in the three modules were combined with a PPI network to identify 31 tumor-specific genes. Hierarchical clustering and Gepia results indicated that the expression quantity of hub genes NDC80, TIPIN, MCM3, MCM6, POLA1, and PRC1 may determine the prognosis of cervical cancer. Finally, TIPIN and POLA1 were further filtered by a LASSO model. In addition, their expression was identified by immunohistochemistry in HPA database as well as a biological experiment.ConclusionOur research provides a co-expression network of gene modules and identifies TIPIN and POLA1 as stable potential prognostic biomarkers for cervical cancer.

Project description:BACKGROUND: Biological networks characterize the interactions of biomolecules at a systems-level. One important property of biological networks is the modular structure, in which nodes are densely connected with each other, but between which there are only sparse connections. In this report, we attempted to find the relationship between the network topology and formation of modular structure by comparing gene co-expression networks with random networks. The organization of gene functional modules was also investigated. RESULTS: We constructed a genome-wide Arabidopsis gene co-expression network (AGCN) by using 1094 microarrays. We then analyzed the topological properties of AGCN and partitioned the network into modules by using an efficient graph clustering algorithm. In the AGCN, 382 hub genes formed a clique, and they were densely connected only to a small subset of the network. At the module level, the network clustering results provide a systems-level understanding of the gene modules that coordinate multiple biological processes to carry out specific biological functions. For instance, the photosynthesis module in AGCN involves a very large number (> 1000) of genes which participate in various biological processes including photosynthesis, electron transport, pigment metabolism, chloroplast organization and biogenesis, cofactor metabolism, protein biosynthesis, and vitamin metabolism. The cell cycle module orchestrated the coordinated expression of hundreds of genes involved in cell cycle, DNA metabolism, and cytoskeleton organization and biogenesis. We also compared the AGCN constructed in this study with a graphical Gaussian model (GGM) based Arabidopsis gene network. The photosynthesis, protein biosynthesis, and cell cycle modules identified from the GGM network had much smaller module sizes compared with the modules found in the AGCN, respectively. CONCLUSION: This study reveals new insight into the topological properties of biological networks. The preferential hub-hub connections might be necessary for the formation of modular structure in gene co-expression networks. The study also reveals new insight into the organization of gene functional modules.

Dataset Information

MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features.

Publications

MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features.

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