736 research outputs found

    A combination of transcriptional and microRNA regulation improves the stability of the relative concentrations of target genes

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    It is well known that, under suitable conditions, microRNAs are able to fine tune the relative concentration of their targets to any desired value. We show that this function is particularly effective when one of the targets is a Transcription Factor (TF) which regulates the other targets. This combination defines a new class of feed-forward loops (FFLs) in which the microRNA plays the role of master regulator. Using both deterministic and stochastic equations we show that these FFLs are indeed able not only to fine-tune the TF/target ratio to any desired value as a function of the miRNA concentration but also, thanks to the peculiar topology of the circuit, to ensures the stability of this ratio against stochastic fluctuations. These two effects are due to the interplay between the direct transcriptional regulation and the indirect TF/Target interaction due to competition of TF and target for miRNA binding (the so called "sponge effect"). We then perform a genome wide search of these FFLs in the human regulatory network and show that they are characterizedby a very peculiar enrichment pattern. In particular they are strongly enriched in all the situations in which the TF and its target have to be precisely kept at the same concentration notwithstanding the environmental noise. As an example we discuss the FFL involving E2F1 as Transcription Factor, RB1 as target and miR-17 family as master regulator. These FFLs ensure a tight control of the E2F/RB ratio which in turns ensures the stability of the transition from the G0/G1 to the S phase in quiescent cells.Comment: 23 pages, 10 figure

    MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors

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    Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF pairs with regulation direction. Subsequently, we determined 288 and 664 dysregulated TF-miRNA-gene FFLs in SE and NSE, respectively. By constructing dysregulated FFL networks, we found that many hub nodes (12 out of 30 for SE and 8 out of 32 for NSE) in the top ranked FFLs could predict subtype-classification (Random Forest classifier, average accuracy ≥90%). These hub molecules were validated by an independent dataset. Our network analysis pinpointed several SE-specific dysregulated miRNAs (miR-200c-3p, miR-25-3p, and miR-302a-3p) and genes (EPHA2, JUN, KLF4, PLXDC2, RND3, SPI1, and TIMP3) and NSE-specific dysregulated miRNAs (miR-367-3p, miR-519d-3p, and miR-96-5p) and genes (NR2F1 and NR2F2). This study is the first systematic investigation of TF and miRNA regulation and their co-regulation in two major TGCT subtypes

    Systems biology-based investigation of cooperating microRNAs as monotherapy or adjuvant therapy in cancer

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    MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer

    MicroRNA modulation networks in Glioblastoma Multiforme subtypes

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    Thesis (M.A.)--Boston UniversityBecause Glioblastoma Multiforme (GBM) usually results in death for most patients diagnosed, it is extremely important to delineate the molecular subtypes of GBM and determine molecular targets for therapy. Though there have been various previous studies that have determined subtypes for GBM, there are no studies that have determined molecular subtypes with a specific gene signature, as well as a specific miRNA signature. This study seeks to expand on the generally accepted and recently discovered subtype determinations, Neural, Proneural, Mesenchymal and Classical by elucidating a miRNA signature for each. In order to determine possible signature miRNAs, functional miRNA-target interactions were integrated with miRNA and mRNA/gene expression to infer mRNA-mediated miRNA-miRNA interactions, using conditional mutual information, for each subtype. The generated network represent miRNA modulation via common target mRNA. Each subtype had a group of most highly connected miRNAs. Because many of these highly connected have experimentally validated evidence linking their regulation or dysregulation in GBM, those without any experimentally validated evidence could also be linked to GBM initiation or progression. Thus, these miRNAs could become future targets for therapeutic discovery and innovation. Further analysis is required to definitively classify miRNAs as linked to GBM in a significant fashion

    The Potential Roles of Long Noncoding RNAs (lncRNA) in Glioblastoma Development

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    Long noncoding RNA (lncRNA) may contribute to the initiation and progression of tumor. In this study, we first systematically compared lncRNA and mRNA expression between glioblastoma and paired normal brain tissues using microarray data. We found 27 lncRNA and 82 mRNA significantly upregulated in glioblastoma, as well as 198 lncRNA and 285 mRNA significantly downregulated in glioblastoma. We identified 138 coexpressed lncRNA–mRNA pairs from these differentially expressed lncRNA and genes. Subsequent pathway analysis of the lncRNA-paired genes indicated that EphrinB–EPHB, p75-mediated signaling, TNFα/NF-κB, and ErbB2/ErbB3 signaling pathways might be altered in glioblastoma. Specifically, lncRNA RAMP2-AS1 had significant decrease of expression in glioblastoma tissues and showed coexpressional relationship with NOTCH3, an important tumor promoter in many neoplastic diseases. Our follow up experiment indicated that (i) an overexpression of RAMP2-AS1 reduced glioblastoma cell proliferation in vitro and also reduced glioblastoma xenograft tumors in vivo; (ii) NOTCH3 and RAMP2-AS1 coexpression rescued the inhibitory action of RAMP2-AS1 in glioblastoma cells; and (iii) RNA pull-down assay revealed a direct interaction of RAMP2-AS1 with DHC10, which may consequently inhibit, as we hypothesize, the expression of NOTCH3 and its downstream signaling molecule HES1 in glioblastoma. Taken together, our data revealed that lncRNA expression profile in glioblastoma tissue was significantly altered; and RAMP2-AS1 might play a tumor suppressive role in glioblastoma through an indirect inhibition of NOTCH3. Our results provided some insights into understanding the key roles of lncRNA–mRNA coregulation in human glioblastoma and the mechanisms responsible for glioblastoma progression and pathogenesis. Mol Cancer Ther; 15(12); 2977–86. ©2016 AACR

    How MicroRNA and Transcription Factor Co-regulatory Networks Affect Osteosarcoma Cell Proliferation

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    Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.​de/co_networks.html)

    BTECH: A Platform to Integrate Genomic, Transcriptomic and Epigenomic Alterations in Brain Tumors

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    The identification of molecular signatures predictive of clinical behavior and outcome in brain tumors has been the focus of many studies in the recent years. Despite the wealth of data that are available in the public domain on alterations in the genome, epigenome and transcriptome of brain tumors, the underlying molecular mechanisms leading to tumor initiation and progression remain largely unknown. Unfortunately, most of these data are scattered in multiple databases and supplementary materials of publications, thus making their retrieval, evaluation, comparison and visualization a rather arduous task. Here we report the development and implementation of an open access database (BTECH), a community resource for the deposition of a wide range of molecular data derived from brain tumor studies. This comprehensive database integrates multiple datasets, including transcript profiles, epigenomic CpG methylation data, DNA copy number alterations and structural chromosomal rearrangements, tumor-associated gene lists, SNPs, genomic features concerning Alu repeats and general genomic annotations. A genome browser has also been developed that allows for the simultaneous visualization of the different datasets and the various annotated features. Besides enabling an integrative view of diverse datasets through the genome browser, we also provide links to the original references for users to have a more accurate understanding of each specific dataset. This integrated platform will facilitate uncovering interactions among genetic and epigenetic factors associated with brain tumor development. BTECH is freely available at http://cmbteg.childrensmemorial.org/. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12021-010-9091-9) contains supplementary material, which is available to authorized users
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