A Rapid Evolving microRNA Cluster Rewires Its Target Regulatory Networks in Drosophila
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ABSTRACT:
SUBMITTER: Lyu Y
PROVIDER: S-EPMC8581666 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Design and implementation of robust network modules is essential for construction of complex biological systems through hierarchical assembly of 'parts' and 'devices'. The robustness of gene regulatory networks (GRNs) is ascribed chiefly to the underlying topology. The automatic designing capability of GRN topology that can exhibit robust behavior can dramatically change the current practice in synthetic biology. A recent study shows that Darwinian evolution can gradually develop higher topological robustness. Subsequently, this work presents an evolutionary algorithm that simulates natural evolution in silico, for identifying network topologies that are robust to perturbations. We present a Monte Carlo based method for quantifying topological robustness and designed a fitness approximation approach for efficient calculation of topological robustness which is computationally very intensive. The proposed framework was verified using two classic GRN behaviors: oscillation and bistability, although the framework is generalized for evolving other types of responses. The algorithm identified robust GRN architectures which were verified using different analysis and comparison. Analysis of the results also shed light on the relationship among robustness, cooperativity and complexity. This study also shows that nature has already evolved very robust architectures for its crucial systems; hence simulation of this natural process can be very valuable for designing robust biological systems.
| S-EPMC4304830 | biostudies-literature
Project description:BACKGROUND: MicroRNAs (miRNAs) play an essential role in gene regulation in plants. At the same time, the expression of miRNA genes is also tightly controlled. Recently, a novel mechanism called "target mimicry" was discovered, providing another layer for modulating miRNA activities. However, except for the artificial target mimics manipulated for functional studies on certain miRNA genes, only one example, IPS1 (Induced by Phosphate Starvation 1)-miR399 was experimentally confirmed in planta. To date, few analyses for comprehensive identification of natural target mimics have been performed in plants. Thus, limited evidences are available to provide detailed information for interrogating the questionable issue whether target mimicry was widespread in planta, and implicated in certain biological processes. RESULTS: In this study, genome-wide computational prediction of endogenous miRNA mimics was performed in Arabidopsis and rice, and dozens of target mimics were identified. In contrast to a recent report, the densities of target mimic sites were found to be much higher within the untranslated regions (UTRs) when compared to those within the coding sequences (CDSs) in both plants. Some novel sequence characteristics were observed for the miRNAs that were potentially regulated by the target mimics. GO (Gene Ontology) term enrichment analysis revealed some functional insights into the predicted mimics. After degradome sequencing data-based identification of miRNA targets, the regulatory networks constituted by target mimics, miRNAs and their downstream targets were constructed, and some intriguing subnetworks were further exploited. CONCLUSIONS: These results together suggest that target mimicry may be widely implicated in regulating miRNA activities in planta, and we hope this study could expand the current understanding of miRNA-involved regulatory networks.
| S-EPMC3441763 | biostudies-literature
Project description:Blood-based microRNA (miRNA) signatures as biomarkers have been reported for various pathologies, including cancer, neurological disorders, cardiovascular diseases, and also infections. The regulatory mechanism behind respective miRNA patterns is only partially understood. Moreover, "preserved" miRNAs, i.e., miRNAs that are not dysregulated in any disease, and their biological impact have been explored to a very limited extent. We set out to systematically determine their role in regulatory networks by defining groups of highly-dysregulated miRNAs that contribute to a disease signature as opposed to preserved housekeeping miRNAs. We further determined preferential targets and pathways of both dysregulated and preserved miRNAs by computing multi-layer networks, which were compared between housekeeping and dysregulated miRNAs. Of 848 miRNAs examined across 1049 blood samples, 8 potential housekeepers showed very limited expression variations, while 20 miRNAs showed highly-dysregulated expression throughout the investigated blood samples. Our approach provides important insights into miRNAs and their role in regulatory networks. The methodology can be applied to systematically investigate the differences in target genes and pathways of arbitrary miRNA sets.
| S-EPMC4563351 | biostudies-literature
Project description:ObjectiveThe aim of the study was to find the key genes, microRNAs (miRNAs) and transcription factors (TFs) and construct miRNA-target gene-TF regulatory networks to investigate the underlying molecular mechanism in colorectal adenoma (CRA).MethodsFour mRNA expression datasets and one miRNA expression dataset were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were identified between CRA and normal samples. Moreover, functional enrichment analysis for DEGs was carried out utilizing the Cytoscape-plugin, known as ClueGO. These DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, a miRNA-target gene regulatory network was established to screen key DEMs. In addition, similar workflow of the analyses were also performed comparing the CRC samples with CRA ones to screen key DEMs. Finally, miRNA-target gene-TF regulatory networks were constructed for these key DEMs using iRegulon plug-in in Cytoscape.ResultsWe identified 514 DEGs and 167 DEMs in CRA samples compared to healthy samples. Functional enrichment analysis revealed that these DEGs were significantly enriched in several terms and pathways, such as regulation of cell migration and bile secretion pathway. A PPI network was constructed including 325 nodes as well as 890 edges. A total of 59 DEGs and 65 DEMs were identified in CRC samples compared to CRA ones. In addition, Two key DEMs in CRA samples compared to healthy samples were identified, such as hsa-miR-34a and hsa-miR-96. One key DEM, hsa-miR-29c, which was identified when we compared the differentially expressed molecules found in the comparison CRA versus normal samples to the ones obtained in the comparison CRC versus CRA, was also identified in CRC samples compared to CRA ones. The miRNA-target gene-TF regulatory networks for these key miRNAs included two TFs, one TF and five TFs, respectively.ConclusionThese identified key genes, miRNA, TFs and miRNA-target gene-TF regulatory networks associated with CRA, to a certain degree, may provide some hints to enable us to better understand the underlying pathogenesis of CRA.
| S-EPMC7248367 | biostudies-literature
Project description:BackgroundMicroRNAs (miRNAs) mediate posttranscriptional regulation of protein-coding genes by binding to the 3' untranslated region of target mRNAs, leading to translational inhibition, mRNA destabilization or degradation, depending on the degree of sequence complementarity. In general, a single miRNA concurrently downregulates hundreds of target mRNAs. Thus, miRNAs play a key role in fine-tuning of diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. However, it remains to be fully elucidated whether a set of miRNA target genes regulated by an individual miRNA in the whole human microRNAome generally constitute the biological network of functionally-associated molecules or simply reflect a random set of functionally-independent genes.MethodsThe complete set of human miRNAs was downloaded from miRBase Release 16. We explored target genes of individual miRNA by using the Diana-microT 3.0 target prediction program, and selected the genes with the miTG score ≧ 20 as the set of highly reliable targets. Then, Entrez Gene IDs of miRNA target genes were uploaded onto KeyMolnet, a tool for analyzing molecular interactions on the comprehensive knowledgebase by the neighboring network-search algorithm. The generated network, compared side by side with human canonical networks of the KeyMolnet library, composed of 430 pathways, 885 diseases, and 208 pathological events, enabled us to identify the canonical network with the most significant relevance to the extracted network.ResultsAmong 1,223 human miRNAs examined, Diana-microT 3.0 predicted reliable targets from 273 miRNAs. Among them, KeyMolnet successfully extracted molecular networks from 232 miRNAs. The most relevant pathway is transcriptional regulation by transcription factors RB/E2F, the disease is adult T cell lymphoma/leukemia, and the pathological event is cancer.ConclusionThe predicted targets derived from approximately 20% of all human miRNAs constructed biologically meaningful molecular networks, supporting the view that a set of miRNA targets regulated by a single miRNA generally constitute the biological network of functionally-associated molecules in human cells.
| S-EPMC3130707 | biostudies-literature
Project description:The proteome expanding effects of alternative pre-mRNA splicing have had a profound impact on eukaryotic evolution. The events that create this diversity can be placed into four major classes: exon skipping, intron retention, alternative 5' splice sites, and alternative 3' splice sites. Although the regulatory mechanisms and evolutionary pressures among alternative splicing classes clearly differ, how these differences affect the evolution of splicing regulation remains poorly characterized. We used RNA-seq to investigate splicing differences in D. simulans, D. sechellia, and three strains of D. melanogaster. Regulation of exon skipping and tandem alternative 3' splice sites (NAGNAGs) were more divergent than other splicing classes. Splicing regulation was most divergent in frame-preserving events and events in noncoding regions. We further determined the contributions of cis- and trans-acting changes in splicing regulatory networks by comparing allele-specific splicing in F1 interspecific hybrids, because differences in allele-specific splicing reflect changes in cis-regulatory element activity. We find that species-specific differences in intron retention and alternative splice site usage are primarily attributable to changes in cis-regulatory elements (median ∼80% cis), whereas species-specific exon skipping differences are driven by both cis- and trans-regulatory divergence (median ∼50% cis). These results help define the mechanisms and constraints that influence splicing regulatory evolution and show that networks regulating the four major classes of alternative splicing diverge through different genetic mechanisms. We propose a model in which differences in regulatory network architecture among classes of alternative splicing affect the evolution of splicing regulation.
| S-EPMC4009608 | biostudies-literature
Project description:ObjectiveThe aim of the current research was to construct a miRNA-transcription factor (TF)-target gene regulatory network in order to investigate the mechanism underlying choriocarcinoma and to verify the network through the overexpression or silencing of hub miRNAs in vitro.Materials and methodsA mRNA expression dataset and two miRNA expression datasets were analysed to identify differentially expressed genes (DEGs) and miRNAs (DEMs) between normal cells and choriocarcinoma cells. The top 400 upregulated and downregulated DEGs were identified as candidate DEGs, which were then mapped to construct protein-protein interaction (PPI) networks and select hub genes. Moreover, the DGIdb database was utilized to select candidate drugs for hub genes. Moreover, DEM target genes were predicted through the miRWalk2.0 database and overlaid with candidate DEGs to identify the differentially expressed target genes (DETGs). Furthermore, we established miRNA-TF-target gene regulatory networks and performed functional enrichment analysis of hub DEMs. Finally, we transfected mimics or inhibitors of hub DEMs into choriocarcinoma cells and assessed cell proliferation and migration to verify the vital role of hub DEMs in choriocarcinoma.ResultsA total of 140 DEMs and 400 candidate DEGs were screened from choriocarcinoma cells and normal cells. A PPI network of 400 candidate DEGs was established. Twenty-nine hub genes and 99 associated small molecules were identified to provide potential target drugs for choriocarcinoma treatment. We obtained 70 DETGs of DEMs derived from the intersection between predicted miRNA target genes and candidate DEGs. Subsequently, 3 hub DEMs were selected, and miRNA-TF-target gene regulatory networks containing 4 TFs, 3 TFs and 3 TFs for each network were constructed. The RT-PCR results confirmed that miR-29b-3p was highly expressed and that miR-519c-3p and miR-520a-5p were expressed at low levels in choriocarcinoma cells. The overexpression or silencing results suggested that 3 dysregulated hub DEMs jointly accelerated the proliferation and migration of choriocarcinoma.ConclusionAssociation of miRNA-TF-target gene regulatory networks may help us explore the underlying mechanism and provide potential targets for the diagnosis and treatment of choriocarcinoma.
| S-EPMC8254590 | biostudies-literature
Project description:BackgroundMicroRNAs (miRNAs) are small non-coding RNAs which play a key role in the post-transcriptional regulation of many genes. Elucidating miRNA-regulated gene networks is crucial for the understanding of mechanisms and functions of miRNAs in many biological processes, such as cell proliferation, development, differentiation and cell homeostasis, as well as in many types of human tumors. To this aim, we have recently presented the biclustering method HOCCLUS2, for the discovery of miRNA regulatory networks. Experiments on predicted interactions revealed that the statistical and biological consistency of the obtained networks is negatively affected by the poor reliability of the output of miRNA target prediction algorithms. Recently, some learning approaches have been proposed to learn to combine the outputs of distinct prediction algorithms and improve their accuracy. However, the application of classical supervised learning algorithms presents two challenges: i) the presence of only positive examples in datasets of experimentally verified interactions and ii) unbalanced number of labeled and unlabeled examples.ResultsWe present a learning algorithm that learns to combine the score returned by several prediction algorithms, by exploiting information conveyed by (only positively labeled/) validated and unlabeled examples of interactions. To face the two related challenges, we resort to a semi-supervised ensemble learning setting. Results obtained using miRTarBase as the set of labeled (positive) interactions and mirDIP as the set of unlabeled interactions show a significant improvement, over competitive approaches, in the quality of the predictions. This solution also improves the effectiveness of HOCCLUS2 in discovering biologically realistic miRNA:mRNA regulatory networks from large-scale prediction data. Using the miR-17-92 gene cluster family as a reference system and comparing results with previous experiments, we find a large increase in the number of significantly enriched biclusters in pathways, consistent with miR-17-92 functions.ConclusionThe proposed approach proves to be fundamental for the computational discovery of miRNA regulatory networks from large-scale predictions. This paves the way to the systematic application of HOCCLUS2 for a comprehensive reconstruction of all the possible multiple interactions established by miRNAs in regulating the expression of gene networks, which would be otherwise impossible to reconstruct by considering only experimentally validated interactions.
| S-EPMC4015287 | biostudies-literature
Project description:BackgroundIn children, retinoblastoma (RB) is one of the most common primary malignant ocular tumors and has a poor prognosis and high mortality. To understand the molecular mechanisms of RB, we identified microRNAs (miRNAs), key genes and transcription factors (TFs) using bioinformatics analysis to build potential miRNA-gene-TF networks.MethodsWe collected three gene expression profiles and one miRNA expression profile from the Gene Expression Omnibus (GEO) database. We used the limma R package to identify overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs in RB tissues compared to noncancer tissues. The robust rank aggregation (RRA) method was implemented to identify key genes among the DEGs. Then, miRNA-key gene-TF networks were built using the online tools TransmiR and miRTarBase. Next, we used RT-qPCR to confirm the results.ResultsWe identified 180 DEGs in RB tissues compared to nontumor tissues using integrative analysis, among which 109 genes were upregulated and 71 were downregulated. Gene ontology (GO) analysis revealed that these DEGs were primarily involved with chromosome segregation, condensed chromosome and DNA replication origin binding. The most highly enriched pathways obtained in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were cell cycle, DNA replication, homologous recombination, P53 signaling pathway and pyrimidine metabolism. Furthermore, two key differentially expressed miRNAs (DEMs) were also established: let-7a and let-7b. Finally, the potential regulatory networks of miRNA-target gene-TFs were examined.ConclusionsThis study identified key genes and built miRNA-target gene-TF regulatory networks in RB, which will deepen our understanding of the molecular mechanisms involved in the development of RB. These key genes and miRNAs may be potential targets and biomarkers for RB diagnosis and therapy.
| S-EPMC9372260 | biostudies-literature
Project description:Sarcopenia is an age-related disease characterized by disturbed homeostasis of skeletal muscle, leading to a decline in muscle mass and function. Loss of muscle mass and strength leads to falls and fracture, and is often accompanied by other geriatric diseases, including osteoporosis, frailty and cachexia, resulting in a general decrease in quality of life and an increase in mortality. Although the underlying mechanisms of sarcopenia are still not completely understood, there has been a marked improvement in the understanding of the pathophysiological changes leading to sarcopenia in recent years. The role of microRNAs (miRNAs), especially, has been clearer in skeletal muscle development and homeostasis. miRNAs form part of a gene regulatory network and have numerous activities in many biological processes. Intervention based on miRNAs may develop into an innovative treatment strategy to conquer sarcopenia. This review is divided into three sections: firstly, the latest understanding of the pathogenesis of sarcopenia is summarized; secondly, increasing evidence for the involvement of miRNAs in the regulation of muscle quantity or quality and muscle homeostasis is highlighted; and thirdly, the possibilities and limitations of miRNAs as a treatment for sarcopenia are explored.
| S-EPMC7205827 | biostudies-literature