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Yang T, He Y, Wang Y. Introducing TEC-LncMir for prediction of lncRNA-miRNA interactions through deep learning of RNA sequences. Brief Bioinform 2024; 26:bbaf046. [PMID: 39927859 PMCID: PMC11808807 DOI: 10.1093/bib/bbaf046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/30/2024] [Accepted: 01/22/2025] [Indexed: 02/11/2025] Open
Abstract
The interactions between long noncoding RNA (lncRNA) and microRNA (miRNA) play critical roles in life processes, highlighting the necessity to enhance the performance of state-of-the-art models. Here, we introduced TEC-LncMir, a novel approach for predicting lncRNA-miRNA interaction using Transformer Encoder and convolutional neural networks (CNNs). TEC-LncMir treats lncRNA and miRNA sequences as natural languages, encodes them using the Transformer Encoder, and combines representations of a pair of microRNA and lncRNA into a contact tensor (a three-dimensional array). Afterward, TEC-LncMir treats the contact tensor as a multi-channel image, utilizes a four-layer CNN to extract the contact tensor's features, and then uses these features to predict the interaction between the pair of lncRNA and miRNA. We applied a series of comparative experiments to demonstrate that TEC-LncMir significantly improves lncRNA-miRNA interaction prediction, compared with existing state-of-the-art models. We also trained TEC-LncMir utilizing a large training dataset, and as expected, TEC-LncMir achieves unprecedented performance. Moreover, we integrated miRanda into TEC-LncMir to show the secondary structures of high-confidence interactions. Finally, we utilized TEC-LncMir to identify microRNAs interacting with lncRNA NEAT1, where NEAT1 performs as a competitive endogenous RNA of the microRNAs' targets (mRNAs) in brain cells. We also demonstrated the regulatory mechanism of NEAT1 in Alzheimer's disease via transcriptome analysis and sequence alignment analysis. Overall, our results demonstrate the effectivity of TEC-LncMir, suggest a potential regulation of miRNAs by NEAT1 in Alzheimer's disease, and take a significant step forward in lncRNA-miRNA interaction prediction.
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Affiliation(s)
- Tingpeng Yang
- Pengcheng Laboratory, No. 2, Xingke 1st Street, Nanshan District, Shenzhen, Guangdong Province 518055, China
- Tsinghua Shenzhen International Graduate School, University Town, Nanshan District, Shenzhen, Guangdong Province 518055, China
| | - Yonghong He
- Pengcheng Laboratory, No. 2, Xingke 1st Street, Nanshan District, Shenzhen, Guangdong Province 518055, China
- Tsinghua Shenzhen International Graduate School, University Town, Nanshan District, Shenzhen, Guangdong Province 518055, China
| | - Yu Wang
- Pengcheng Laboratory, No. 2, Xingke 1st Street, Nanshan District, Shenzhen, Guangdong Province 518055, China
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2
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Yang T, Wang Y, He Y. TEC-miTarget: enhancing microRNA target prediction based on deep learning of ribonucleic acid sequences. BMC Bioinformatics 2024; 25:159. [PMID: 38643080 PMCID: PMC11032603 DOI: 10.1186/s12859-024-05780-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 04/12/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND MicroRNAs play a critical role in regulating gene expression by binding to specific target sites within gene transcripts, making the identification of microRNA targets a prominent focus of research. Conventional experimental methods for identifying microRNA targets are both time-consuming and expensive, prompting the development of computational tools for target prediction. However, the existing computational tools exhibit limited performance in meeting the demands of practical applications, highlighting the need to improve the performance of microRNA target prediction models. RESULTS In this paper, we utilize the most popular natural language processing and computer vision technologies to propose a novel approach, called TEC-miTarget, for microRNA target prediction based on transformer encoder and convolutional neural networks. TEC-miTarget treats RNA sequences as a natural language and encodes them using a transformer encoder, a widely used encoder in natural language processing. It then combines the representations of a pair of microRNA and its candidate target site sequences into a contact map, which is a three-dimensional array similar to a multi-channel image. Therefore, the contact map's features are extracted using a four-layer convolutional neural network, enabling the prediction of interactions between microRNA and its candidate target sites. We applied a series of comparative experiments to demonstrate that TEC-miTarget significantly improves microRNA target prediction, compared with existing state-of-the-art models. Our approach is the first approach to perform comparisons with other approaches at both sequence and transcript levels. Furthermore, it is the first approach compared with both deep learning-based and seed-match-based methods. We first compared TEC-miTarget's performance with approaches at the sequence level, and our approach delivers substantial improvements in performance using the same datasets and evaluation metrics. Moreover, we utilized TEC-miTarget to predict microRNA targets in long mRNA sequences, which involves two steps: selecting candidate target site sequences and applying sequence-level predictions. We finally showed that TEC-miTarget outperforms other approaches at the transcript level, including the popular seed match methods widely used in previous years. CONCLUSIONS We propose a novel approach for predicting microRNA targets at both sequence and transcript levels, and demonstrate that our approach outperforms other methods based on deep learning or seed match. We also provide our approach as an easy-to-use software, TEC-miTarget, at https://github.com/tingpeng17/TEC-miTarget . Our results provide new perspectives for microRNA target prediction.
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Affiliation(s)
- Tingpeng Yang
- Peng Cheng Laboratory, Shenzhen, 518055, China
- Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Yu Wang
- Peng Cheng Laboratory, Shenzhen, 518055, China.
| | - Yonghong He
- Peng Cheng Laboratory, Shenzhen, 518055, China.
- Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
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3
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The EMT activator ZEB1 accelerates endosomal trafficking to establish a polarity axis in lung adenocarcinoma cells. Nat Commun 2021; 12:6354. [PMID: 34732702 PMCID: PMC8566461 DOI: 10.1038/s41467-021-26677-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion. Dynamic assembly of focal adhesions and other actin-based cytoskeletal structures on the leading edge of motile cells requires precise spatial and temporal control of protein trafficking. Yet, the way in which EMT-activating transcriptional programs interface with vesicular trafficking networks that effect cell polarity change remains unclear. Here, by utilizing multiple approaches to assess vesicular transport dynamics through endocytic recycling and retrograde trafficking pathways in lung adenocarcinoma cells at distinct positions on the EMT spectrum, we find that the EMT-activating transcription factor ZEB1 accelerates endocytosis and intracellular trafficking of plasma membrane-bound proteins. ZEB1 drives turnover of the MET receptor tyrosine kinase by hastening receptor endocytosis and transport to the lysosomal compartment for degradation. ZEB1 relieves a plus-end-directed microtubule-dependent kinesin motor protein (KIF13A) and a clathrin-associated adaptor protein complex subunit (AP1S2) from microRNA-dependent silencing, thereby accelerating cargo transport through the endocytic recycling and retrograde vesicular pathways, respectively. Depletion of KIF13A or AP1S2 mitigates ZEB1-dependent focal adhesion dynamics, front-rear axis polarization, and cancer cell motility. Thus, ZEB1-dependent transcriptional networks govern vesicular trafficking dynamics to effect cell polarity change. The way in which metastatic tumour cells control endocytic vesicular trafficking networks to establish a front-rear polarity axis that facilitates motility remains unclear. Here, the authors show that the EMT activator ZEB1 influences vesicular trafficking dynamics to execute cell polarity change.
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4
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Fishman ES, Louie M, Miltner AM, Cheema SK, Wong J, Schlaeger NM, Moshiri A, Simó S, Tarantal AF, La Torre A. MicroRNA Signatures of the Developing Primate Fovea. Front Cell Dev Biol 2021; 9:654385. [PMID: 33898453 PMCID: PMC8060505 DOI: 10.3389/fcell.2021.654385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/16/2021] [Indexed: 11/22/2022] Open
Abstract
Rod and cone photoreceptors differ in their shape, photopigment expression, synaptic connection patterns, light sensitivity, and distribution across the retina. Although rods greatly outnumber cones, human vision is mostly dependent on cone photoreceptors since cones are essential for our sharp visual acuity and color discrimination. In humans and other primates, the fovea centralis (fovea), a specialized region of the central retina, contains the highest density of cones. Despite the vast importance of the fovea for human vision, the molecular mechanisms guiding the development of this region are largely unknown. MicroRNAs (miRNAs) are small post-transcriptional regulators known to orchestrate developmental transitions and cell fate specification in the retina. Here, we have characterized the transcriptional landscape of the developing rhesus monkey retina. Our data indicates that non-human primate fovea development is significantly accelerated compared to the equivalent retinal region at the other side of the optic nerve head, as described previously. Notably, we also identify several miRNAs differentially expressed in the presumptive fovea, including miR-15b-5p, miR-342-5p, miR-30b-5p, miR-103-3p, miR-93-5p as well as the miRNA cluster miR-183/-96/-182. Interestingly, miR-342-5p is enriched in the nasal primate retina and in the peripheral developing mouse retina, while miR-15b is enriched in the temporal primate retina and increases over time in the mouse retina in a central-to-periphery gradient. Together our data constitutes the first characterization of the developing rhesus monkey retinal miRNome and provides novel datasets to attain a more comprehensive understanding of foveal development.
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Affiliation(s)
- Elizabeth S Fishman
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Mikaela Louie
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Adam M Miltner
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Simranjeet K Cheema
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Joanna Wong
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Nicholas M Schlaeger
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Ala Moshiri
- Department of Ophthalmology, University of California, Davis, Davis, CA, United States
| | - Sergi Simó
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Alice F Tarantal
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States.,Department of Pediatrics, University of California, Davis, Davis, CA, United States.,California National Primate Research Center, University of California, Davis, Davis, CA, United States
| | - Anna La Torre
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
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5
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Liu N, Wei S, Zhao R. Integrated miRNA-mRNA Analysis Reveals Potential Biomarkers of Chemoresistance in Ovarian Cancer. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The current study aimed to determine potential biomarkers related to chemoresistance in ovarian cancer and the involved signaling pathways through bioinformatics analysis. This was followed by an exploration of the related indices on the occurrence and development of chemoresistance
in ovarian cancer (OC). Five miRNA/mRNA expression datasets on chemoresistance OC were obtained from the Geodatabase. The significantly different expressed miRNAs (DEMs) and differently expressed genes (DEGs) between chemoresistant OC tissues and control tissues were screened using the GEO2R
online tool. Afterwards, pathway analysis was utilized to analyze the DEGs and Cytoscape with STRING 11.0 was used to visualize the protein-protein interaction (PPI) network of DEGs. Afterwards, TFmiR webserver was performed to predict the TF-miRNA-mRNA network. Finally, KM-Plotter was utilized
to determine the effects of hub genes and key miRNAs on survival time. A total of 24 DEMs and 548 DEGs were screened from four different datasets on chemoresistance in OC. Seven mRNA-miRNA pairs were found. Survival analysis based on the Kaplan-Meier plotter revealed that 11 biomarkers, including
hsa-miR-363, hsa-miR-125b, CDKN1N, JUN, KFL4, IGFBP3, TGFBR2, CCR5, SPP1, LOX, and MMP1, which were associated with TF-miRNA-mRNA network, were closely associated with overall survival (OS) in patients with OC (P< 0.05). The integrated genomic analysis method was successful in screening
novel and important genes for the occurrence and progression of chemoresistance in OC. Moreover, this method provided valuable information for investigating chemoresistance in OC and also forms the basis for further functional research.
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Affiliation(s)
- Niping Liu
- Department of Gynecology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi, China
| | - Shiyang Wei
- Department of Gynecology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi, China
| | - Renfeng Zhao
- Department of Gynecology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi, China
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Yoon S, Nguyen HCT, Jo W, Kim J, Chi SM, Park J, Kim SY, Nam D. Biclustering analysis of transcriptome big data identifies condition-specific microRNA targets. Nucleic Acids Res 2019; 47:e53. [PMID: 30820547 PMCID: PMC6511842 DOI: 10.1093/nar/gkz139] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 02/19/2019] [Indexed: 12/26/2022] Open
Abstract
We present a novel approach to identify human microRNA (miRNA) regulatory modules (mRNA targets and relevant cell conditions) by biclustering a large collection of mRNA fold-change data for sequence-specific targets. Bicluster targets were assessed using validated messenger RNA (mRNA) targets and exhibited on an average 17.0% (median 19.4%) improved gain in certainty (sensitivity + specificity). The net gain was further increased up to 32.0% (median 33.4%) by incorporating functional networks of targets. We analyzed cancer-specific biclusters and found that the PI3K/Akt signaling pathway is strongly enriched with targets of a few miRNAs in breast cancer and diffuse large B-cell lymphoma. Indeed, five independent prognostic miRNAs were identified, and repression of bicluster targets and pathway activity by miR-29 was experimentally validated. In total, 29 898 biclusters for 459 human miRNAs were collected in the BiMIR database where biclusters are searchable for miRNAs, tissues, diseases, keywords and target genes.
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Affiliation(s)
- Sora Yoon
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Hai C T Nguyen
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Woobeen Jo
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Jinhwan Kim
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Sang-Mun Chi
- School of Computer Science and Engineering, Kyungsung University, Busan 48434, Republic of Korea
| | - Jiyoung Park
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Seon-Young Kim
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Republic of Korea.,Genome Editing Research Center, Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Dougu Nam
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.,Department of Mathematical Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
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7
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Lei H, Liu W, Si J, Wang J, Zhang T. Analyzing the regulation of miRNAs on protein-protein interaction network in Hodgkin lymphoma. BMC Bioinformatics 2019; 20:449. [PMID: 31477006 PMCID: PMC6720096 DOI: 10.1186/s12859-019-3041-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 08/21/2019] [Indexed: 12/28/2022] Open
Abstract
Background Hodgkin Lymphoma (HL) is a type of aggressive malignancy in lymphoma that has high incidence in young adults and elderly patients. Identification of reliable diagnostic markers and efficient therapeutic targets are especially important for the diagnosis and treatment of HL. Although many HL-related molecules have been identified, our understanding on the molecular mechanisms underlying the disease is still far from complete due to its complex and heterogeneous characteristics. In such situation, exploring the molecular mechanisms underlying HL via systems biology approaches provides a promising option. In this study, we try to elucidate the molecular mechanisms related to the disease and identify potential pharmaceutical targets from a network-based perspective. Results We constructed a series of network models. Based on the analysis of these networks, we attempted to identify the biomarkers and elucidate the molecular mechanisms underlying HL. Initially, we built three different but related protein networks, i.e., background network, HL-basic network and HL-specific network. By analyzing these three networks, we investigated the connection characteristic of the HL-related proteins. Subsequently, we explored the miRNA regulation on HL-specific network and analyzed three kinds of simple regulation patterns, i.e., co-regulation of protein pairs, as well as the direct and indirect regulation of triple proteins. Finally, we constructed a simplified protein network combined with the regulation of miRNAs on proteins to better understand the relation between HL-related proteins and miRNAs. Conclusions We find that the HL-related proteins are more likely to connect with each other compared to other proteins. Moreover, the HL-specific network can be further divided into five sub-networks and 49 proteins as the backbone of HL-specific network make up and connect these 5 sub-networks. Thus, they may be closely associated with HL. In addition, we find that the co-regulation of protein pairs is the main regulatory pattern of miRNAs on the protein network in the HL-specific network. According to the regulation of miRNA on protein network, we have identified 5 core miRNAs as the potential biomarkers for diagnostic of HL. Finally, several protein pathways have been identified to closely associated with HL, which provides deep insights into underlying mechanism of HL. Electronic supplementary material The online version of this article (10.1186/s12859-019-3041-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Huimin Lei
- School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.,School of Continuation Education, Tianjin Medical University, Tianjin, China
| | - Wenxu Liu
- School of Biomedical Engineering, Tianjin Medical University, Tianjin, China
| | - Jiarui Si
- School of Basic Medicine, Tianjin Medical University, Tianjin, China
| | - Ju Wang
- School of Biomedical Engineering, Tianjin Medical University, Tianjin, China
| | - Tao Zhang
- School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.
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8
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Kinetic Modelling of Competition and Depletion of Shared miRNAs by Competing Endogenous RNAs. Methods Mol Biol 2019; 1912:367-409. [PMID: 30635902 DOI: 10.1007/978-1-4939-8982-9_15] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Non-coding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting, e.g., the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.
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9
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In silico identification of microRNAs predicted to regulate N-myristoyltransferase and Methionine Aminopeptidase 2 functions in cancer and infectious diseases. PLoS One 2018; 13:e0194612. [PMID: 29579063 PMCID: PMC5868815 DOI: 10.1371/journal.pone.0194612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 03/06/2018] [Indexed: 01/16/2023] Open
Abstract
Protein myristoylation is a key protein modification carried out by N-Myristoyltransferase (NMT) after Methionine aminopeptidase 2 (MetAP2) removes methionine from the amino-terminus of the target protein. Protein myristoylation by NMT augments several signaling pathways involved in a myriad of cellular processes, including developmental pathways and pathways that when dysregulated lead to cancer or immune dysfunction. The emerging evidence pointing to NMT-mediated myristoylation as a major cellular regulator underscores the importance of understanding the framework of this type of signaling event. Various studies have investigated the role that myristoylation plays in signaling dysfunction by examining differential gene or protein expression between normal and diseased states, such as cancers or following HIV-1 infection, however no study exists that addresses the role of microRNAs (miRNAs) in the regulation of myristoylation. By performing a large scale bioinformatics and functional analysis of the miRNAs that target key genes involved in myristoylation (NMT1, NMT2, MetAP2), we have narrowed down a list of promising candidates for further analysis. Our condensed panel of miRNAs identifies 35 miRNAs linked to cancer, 21 miRNAs linked to developmental and immune signaling pathways, and 14 miRNAs linked to infectious disease (primarily HIV). The miRNAs panel that was analyzed revealed several NMT-targeting mRNAs (messenger RNA) that are implicated in diseases associated with NMT signaling alteration, providing a link between the realms of miRNA and myristoylation signaling. These findings verify miRNA as an additional facet of myristoylation signaling that must be considered to gain a full perspective. This study provides the groundwork for future studies concerning NMT-transcript-binding miRNAs, and will potentially lead to the development of new diagnostic/prognostic biomarkers and therapeutic targets for several important diseases.
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10
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Lu M, Xu X, Xi B, Dai Q, Li C, Su L, Zhou X, Tang M, Yao Y, Yang J. Molecular Network-Based Identification of Competing Endogenous RNAs in Thyroid Carcinoma. Genes (Basel) 2018; 9:E44. [PMID: 29351231 PMCID: PMC5793195 DOI: 10.3390/genes9010044] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/10/2018] [Accepted: 01/11/2018] [Indexed: 12/14/2022] Open
Abstract
RNAs may act as competing endogenous RNAs (ceRNAs), a critical mechanism in determining gene expression regulations in many cancers. However, the roles of ceRNAs in thyroid carcinoma remains elusive. In this study, we have developed a novel pipeline called Molecular Network-based Identification of ceRNA (MNIceRNA) to identify ceRNAs in thyroid carcinoma. MNIceRNA first constructs micro RNA (miRNA)-messenger RNA (mRNA)long non-coding RNA (lncRNA) networks from miRcode database and weighted correlation network analysis (WGCNA), based on which to identify key drivers of differentially expressed RNAs between normal and tumor samples. It then infers ceRNAs of the identified key drivers using the long non-coding competing endogenous database (lnCeDB). We applied the pipeline into The Cancer Genome Atlas (TCGA) thyroid carcinoma data. As a result, 598 lncRNAs, 1025 mRNAs, and 90 microRNA (miRNAs) were inferred to be differentially expressed between normal and thyroid cancer samples. We then obtained eight key driver miRNAs, among which hsa-mir-221 and hsa-mir-222 were key driver RNAs identified by both miRNA-mRNA-lncRNA and WGCNA network. In addition, hsa-mir-375 was inferred to be significant for patients' survival with 34 associated ceRNAs, among which RUNX2, DUSP6 and SEMA3D are known oncogenes regulating cellular proliferation and differentiation in thyroid cancer. These ceRNAs are critical in revealing the secrets behind thyroid cancer progression and may serve as future therapeutic biomarkers.
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Affiliation(s)
- Minjia Lu
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
| | - Xingyu Xu
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
| | - Baohang Xi
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
| | - Qi Dai
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
| | - Chenli Li
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China.
| | - Li Su
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China.
| | - Xiaonan Zhou
- Institute of Basic Medical Sciences, Wannan Medical College, Hefei 241000, China.
| | - Min Tang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
| | - Yuhua Yao
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China.
| | - Jialiang Yang
- School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China.
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
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11
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Boone DK, Weisz HA, Bi M, Falduto MT, Torres KEO, Willey HE, Volsko CM, Kumar AM, Micci MA, Dewitt DS, Prough DS, Hellmich HL. Evidence linking microRNA suppression of essential prosurvival genes with hippocampal cell death after traumatic brain injury. Sci Rep 2017; 7:6645. [PMID: 28751711 PMCID: PMC5532254 DOI: 10.1038/s41598-017-06341-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 06/13/2017] [Indexed: 01/09/2023] Open
Abstract
The underlying molecular mechanisms of how dysregulated microRNAs (miRNAs) cause neurodegeneration after traumatic brain injury (TBI) remain elusive. Here we analyzed the biological roles of approximately 600 genes - we previously found these dysregulated in dying and surviving rat hippocampal neurons - that are targeted by ten TBI-altered miRNAs. Bioinformatic analysis suggests that neurodegeneration results from a global miRNA-mediated suppression of genes essential for maintaining proteostasis; many are hub genes - involved in RNA processing, cytoskeletal metabolism, intracellular trafficking, cell cycle progression, repair/maintenance, bioenergetics and cell-cell signaling - whose disrupted expression is linked to human disease. Notably, dysregulation of these essential genes would significantly impair synaptic function and functional brain connectivity. In surviving neurons, upregulated miRNA target genes are co-regulated members of prosurvival pathways associated with cellular regeneration, neural plasticity, and development. This study captures the diversity of miRNA-regulated genes that may be essential for cell repair and survival responses after TBI.
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Affiliation(s)
- Deborah Kennedy Boone
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Harris A Weisz
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Min Bi
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | | | | | - Hannah E Willey
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Christina M Volsko
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Anjali M Kumar
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Maria-Adelaide Micci
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Douglas S Dewitt
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Donald S Prough
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Helen L Hellmich
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA.
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12
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He SJ, Xiang CQ, Zhang Y, Lu XT, Chen HW, Xiong LX. Recent progress on the effects of microRNAs and natural products on tumor epithelial-mesenchymal transition. Onco Targets Ther 2017; 10:3435-3451. [PMID: 28744148 PMCID: PMC5513877 DOI: 10.2147/ott.s139546] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a biological process of phenotypic transition of epithelial cells that can promote physiological development as well as tissue healing and repair. In recent years, cancer researchers have noted that EMT is closely related to the occurrence and development of tumors. When tumor cells undergo EMT, they can develop enhanced migration and local tissue invasion abilities, which can lead to metastatic growth. Nevertheless, two researches in NATURE deny its necessity in specific tumors and that is discussed in this review. The degree of EMT and the detection of EMT-associated marker molecules can also be used to judge the risk of metastasis and to evaluate patients’ prognosis. MicroRNAs (miRNAs) are noncoding small RNAs, which can inhibit gene expression and protein translation through specific binding with the 3′ untranslated region of mRNA. In this review, we summarize the miRNAs that are reported to influence EMT through transcription factors such as ZEB, SNAIL, and TWIST, as well as some natural products that regulate EMT in tumors. Moreover, mutual inhibition occurs between some transcription factors and miRNAs, and these effects appear to occur in a complex regulatory network. Thus, understanding the role of miRNAs in EMT and tumor growth may lead to new treatments for malignancies. Natural products can also be combined with conventional chemotherapy to enhance curative effects.
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Affiliation(s)
- Shu-Jin He
- Department of Pathophysiology, Medical College, Nanchang University.,Second Clinical Medical College, Nanchang University
| | - Chu-Qi Xiang
- Department of Pathophysiology, Medical College, Nanchang University.,First Clinical Medical College, Nanchang University
| | - Yu Zhang
- First Clinical Medical College, Nanchang University
| | - Xiang-Tong Lu
- Department of Pathophysiology, Medical College, Nanchang University
| | - Hou-Wen Chen
- Department of Pathophysiology, Medical College, Nanchang University.,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, People's Republic of China
| | - Li-Xia Xiong
- Department of Pathophysiology, Medical College, Nanchang University.,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, People's Republic of China
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13
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Martirosyan A, De Martino A, Pagnani A, Marinari E. ceRNA crosstalk stabilizes protein expression and affects the correlation pattern of interacting proteins. Sci Rep 2017; 7:43673. [PMID: 28266541 PMCID: PMC5339858 DOI: 10.1038/srep43673] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 01/27/2017] [Indexed: 12/14/2022] Open
Abstract
Gene expression is a noisy process and several mechanisms, both transcriptional and post-transcriptional, can stabilize protein levels in cells. Much work has focused on the role of miRNAs, showing in particular that miRNA-mediated regulation can buffer expression noise for lowly expressed genes. Here, using in silico simulations and mathematical modeling, we demonstrate that miRNAs can exert a much broader influence on protein levels by orchestrating competition-induced crosstalk between mRNAs. Most notably, we find that miRNA-mediated cross-talk (i) can stabilize protein levels across the full range of gene expression rates, and (ii) modifies the correlation pattern of co-regulated interacting proteins, changing the sign of correlations from negative to positive. The latter feature may constitute a potentially robust signature of the existence of RNA crosstalk induced by endogenous competition for miRNAs in standard cellular conditions.
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Affiliation(s)
| | - Andrea De Martino
- Soft &Living Matter Lab, Istituto di Nanotecnologia (NANOTEC-CNR), Rome, Italy.,Human Genetics Foundation, Turin, Italy.,Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Andrea Pagnani
- Human Genetics Foundation, Turin, Italy.,Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, Turin, Italy
| | - Enzo Marinari
- Dipartimento di Fisica, Sapienza Università di Roma, Rome, Italy.,INFN, Sezione di Roma 1, Rome, Italy
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14
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Bracken CP, Scott HS, Goodall GJ. A network-biology perspective of microRNA function and dysfunction in cancer. Nat Rev Genet 2016; 17:719-732. [DOI: 10.1038/nrg.2016.134] [Citation(s) in RCA: 529] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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15
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Tkatchenko AV, Luo X, Tkatchenko TV, Vaz C, Tanavde VM, Maurer-Stroh S, Zauscher S, Gonzalez P, Young TL. Large-Scale microRNA Expression Profiling Identifies Putative Retinal miRNA-mRNA Signaling Pathways Underlying Form-Deprivation Myopia in Mice. PLoS One 2016; 11:e0162541. [PMID: 27622715 PMCID: PMC5021328 DOI: 10.1371/journal.pone.0162541] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 08/24/2016] [Indexed: 12/16/2022] Open
Abstract
Development of myopia is associated with large-scale changes in ocular tissue gene expression. Although differential expression of coding genes underlying development of myopia has been a subject of intense investigation, the role of non-coding genes such as microRNAs in the development of myopia is largely unknown. In this study, we explored myopia-associated miRNA expression profiles in the retina and sclera of C57Bl/6J mice with experimentally induced myopia using microarray technology. We found a total of 53 differentially expressed miRNAs in the retina and no differences in miRNA expression in the sclera of C57BL/6J mice after 10 days of visual form deprivation, which induced -6.93 ± 2.44 D (p < 0.000001, n = 12) of myopia. We also identified their putative mRNA targets among mRNAs found to be differentially expressed in myopic retina and potential signaling pathways involved in the development of form-deprivation myopia using miRNA-mRNA interaction network analysis. Analysis of myopia-associated signaling pathways revealed that myopic response to visual form deprivation in the retina is regulated by a small number of highly integrated signaling pathways. Our findings highlighted that changes in microRNA expression are involved in the regulation of refractive eye development and predicted how they may be involved in the development of myopia by regulating retinal gene expression.
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Affiliation(s)
- Andrei V. Tkatchenko
- Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- * E-mail: (AVT); (TLY)
| | - Xiaoyan Luo
- Department of Ophthalmology, School of Medicine, Duke University, Durham, North Carolina, United States of America
- Center for Human Genetics, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Tatiana V. Tkatchenko
- Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Candida Vaz
- Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore
| | - Vivek M. Tanavde
- Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore
- Institute for Medical Biology, A*STAR, Singapore, Singapore
| | - Sebastian Maurer-Stroh
- Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore
| | - Stefan Zauscher
- Department of Mechanical Engineering and Materials Science, Pratt School of Engineering, Duke University, Durham, North Carolina, United States of America
| | - Pedro Gonzalez
- Department of Ophthalmology, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Terri L. Young
- Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America
- * E-mail: (AVT); (TLY)
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16
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Lai M, Gonzalez-Martin A, Cooper AB, Oda H, Jin HY, Shepherd J, He L, Zhu J, Nemazee D, Xiao C. Regulation of B-cell development and tolerance by different members of the miR-17∼92 family microRNAs. Nat Commun 2016; 7:12207. [PMID: 27481093 PMCID: PMC4974641 DOI: 10.1038/ncomms12207] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 06/10/2016] [Indexed: 12/19/2022] Open
Abstract
The molecular mechanisms that regulate B-cell development and tolerance remain incompletely understood. In this study, we identify a critical role for the miR-17∼92 microRNA cluster in regulating B-cell central tolerance and demonstrate that these miRNAs control early B-cell development in a cell-intrinsic manner. While the cluster member miR-19 suppresses the expression of Pten and plays a key role in regulating B-cell tolerance, miR-17 controls early B-cell development through other molecular pathways. These findings demonstrate differential control of two closely linked B-cell developmental stages by different members of a single microRNA cluster through distinct molecular pathways. MicroRNA cluster 17∼92 plays a critical role in B-cell differentiation. Here the authors show that miR-19 regulates B-cell tolerance via suppressing the expression of PTEN, whereas miR- 17 is essential for early B-cell development independently of Pten, Phlpp2, or Bim.
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Affiliation(s)
- Maoyi Lai
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Alicia Gonzalez-Martin
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Anthony B Cooper
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Hiroyo Oda
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Hyun Yong Jin
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.,Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California 92037, USA
| | - Jovan Shepherd
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Linling He
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Jiang Zhu
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - David Nemazee
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
| | - Changchun Xiao
- Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
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17
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Preusse M, Marr C, Saunders S, Maticzka D, Lickert H, Backofen R, Theis F. SimiRa: A tool to identify coregulation between microRNAs and RNA-binding proteins. RNA Biol 2016; 12:998-1009. [PMID: 26383775 PMCID: PMC4615630 DOI: 10.1080/15476286.2015.1068496] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
microRNAs and microRNA-independent RNA-binding proteins are 2 classes of post-transcriptional regulators that have been shown to cooperate in gene-expression regulation. We compared the genome-wide target sets of microRNAs and RBPs identified by recent CLIP-Seq technologies, finding that RBPs have distinct target sets and favor gene interaction network hubs. To identify microRNAs and RBPs with a similar functional context, we developed simiRa, a tool that compares enriched functional categories such as pathways and GO terms. We applied simiRa to the known functional cooperation between Pumilio family proteins and miR-221/222 in the regulation of tumor supressor gene p27 and show that the cooperation is reflected by similar enriched categories but not by target genes. SimiRa also predicts possible cooperation of microRNAs and RBPs beyond direct interaction on the target mRNA for the nuclear RBP TAF15. To further facilitate research into cooperation of microRNAs and RBPs, we made simiRa available as a web tool that displays the functional neighborhood and similarity of microRNAs and RBPs: http://vsicb-simira.helmholtz-muenchen.de.
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Affiliation(s)
- Martin Preusse
- a Helmholtz Zentrum München - German Research Center for Environmental Health; Institute of Computational Biology ; Neuherberg , Germany.,b Helmholtz Zentrum München - German Research Center for Environmental Health; Institute of Diabetes and Regeneration Research ; Neuherberg , Germany
| | - Carsten Marr
- a Helmholtz Zentrum München - German Research Center for Environmental Health; Institute of Computational Biology ; Neuherberg , Germany
| | - Sita Saunders
- c Bioinformatics; Department of Computer Science; University of Freiburg ; Freiburg , Germany
| | - Daniel Maticzka
- c Bioinformatics; Department of Computer Science; University of Freiburg ; Freiburg , Germany
| | - Heiko Lickert
- b Helmholtz Zentrum München - German Research Center for Environmental Health; Institute of Diabetes and Regeneration Research ; Neuherberg , Germany.,d Medical Faculty; Technische Universität München ; Munich , Germany
| | - Rolf Backofen
- c Bioinformatics; Department of Computer Science; University of Freiburg ; Freiburg , Germany.,e BIOSS Center for Biological Signaling Studies; Cluster of Excellence; University of Freiburg ; Freiburg , Germany
| | - Fabian Theis
- b Helmholtz Zentrum München - German Research Center for Environmental Health; Institute of Diabetes and Regeneration Research ; Neuherberg , Germany.,f Technische Universität München; Center for Mathematics; Chair of Mathematical Modeling of Biological Systems ; Garching , Germany
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18
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MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2015; 16:30204-22. [PMID: 26694379 PMCID: PMC4691172 DOI: 10.3390/ijms161226230] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 12/08/2015] [Accepted: 12/09/2015] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method “miRlastic”, which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of miRNAs that were predicted to mediate HPV-associated dysregulation in HNSCC. Our novel approach was able to characterize distinct pathway regulations from matched miRNA and mRNA data. An R package of miRlastic was made available through: http://icb.helmholtz-muenchen.de/mirlastic.
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19
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Zhang J, Le TD, Liu L, He J, Li J. A novel framework for inferring condition-specific TF and miRNA co-regulation of protein-protein interactions. Gene 2015; 577:55-64. [PMID: 26611531 DOI: 10.1016/j.gene.2015.11.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 10/16/2015] [Accepted: 11/17/2015] [Indexed: 12/11/2022]
Abstract
Recent studies have shown that transcription factors (TFs) and microRNAs (miRNAs), while independently regulate their downstream targets, collaborate with each other to regulate gene expression. However, their synergistic roles in protein-protein interactions (PPIs) remain mostly unknown. In this paper, we present a novel framework (called CoRePPI) for inferring TF and miRNA co-regulation of PPIs. Particularly, CoRePPI is aimed at discovering the co-regulation specific to a condition of interest, by using heterogeneous data, including miRNA and messenger RNA (mRNA) expression profiles, putative miRNA targets, TF targets and PPIs. CoRePPI firstly finds the network motifs indicating the co-regulation of PPIs by TFs and miRNAs in tumor and normal conditions separately. Then by identifying the differential motifs found in one condition but not in the other, it builds the networks consisting of TFs, miRNAs and their co-regulated PPIs specific to different conditions respectively. To validate CoRePPI, we apply it to the Pan-Cancer dataset which includes the expression profiles of 12 cancer types from TCGA. Through network topology analysis, we found that the tumor and normal CoRePPI networks are scale-free. Furthermore, the results of differential and intersected network analysis between the tumor and normal CoRePPI networks suggest that only a small fraction of the regulatory relationships between TFs and miRNAs are conserved in both conditions but they co-regulate different downstream PPIs in tumor and normal conditions; and in different conditions the majority of the regulatory relationships between TFs and miRNAs are different although they may regulate the same PPIs in their respective conditions. The CoRePPI sub-networks constructed for the three types of cancers (breast cancer, lung cancer and ovarian cancer) are all scale-free, and the intersection of these CoRePPI sub-networks can be utilized as the biomarker CoRePPI sub-network of the three types of cancers. The PPI enrichment analyses of the tumor and normal CoRePPI networks suggest that the co-regulating TFs and miRNAs are significantly associated with the specific biological processes, diseases and pathways. In addition, comparing with the two non-condition-specific approaches, the tumor CoRePPI network is found to have the most enriched cancer-related PPIs. Altogether, the results uncover the combined regulatory patterns of TFs and miRNAs on the PPIs, and may provide new insights for research in cancer-associated TFs and miRNAs.
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Affiliation(s)
- Junpeng Zhang
- School of Engineering, Dali University, Dali, Yunnan 671003, China.
| | - Thuc Duy Le
- School of Information Technology and Mathematical Sciences, University of South Australia, Mawson Lakes, SA 5095, Australia
| | - Lin Liu
- School of Information Technology and Mathematical Sciences, University of South Australia, Mawson Lakes, SA 5095, Australia
| | - Jianfeng He
- School of Information Engineering and Automation, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Jiuyong Li
- School of Information Technology and Mathematical Sciences, University of South Australia, Mawson Lakes, SA 5095, Australia.
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20
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Meyer SU, Sass S, Mueller NS, Krebs S, Bauersachs S, Kaiser S, Blum H, Thirion C, Krause S, Theis FJ, Pfaffl MW. Integrative Analysis of MicroRNA and mRNA Data Reveals an Orchestrated Function of MicroRNAs in Skeletal Myocyte Differentiation in Response to TNF-α or IGF1. PLoS One 2015; 10:e0135284. [PMID: 26270642 PMCID: PMC4536022 DOI: 10.1371/journal.pone.0135284] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 07/20/2015] [Indexed: 12/23/2022] Open
Abstract
Introduction Skeletal muscle cell differentiation is impaired by elevated levels of the inflammatory cytokine tumor necrosis factor-α (TNF-α) with pathological significance in chronic diseases or inherited muscle disorders. Insulin like growth factor-1 (IGF1) positively regulates muscle cell differentiation. Both, TNF-α and IGF1 affect gene and microRNA (miRNA) expression in this process. However, computational prediction of miRNA-mRNA relations is challenged by false positives and targets which might be irrelevant in the respective cellular transcriptome context. Thus, this study is focused on functional information about miRNA affected target transcripts by integrating miRNA and mRNA expression profiling data. Methodology/Principal Findings Murine skeletal myocytes PMI28 were differentiated for 24 hours with concomitant TNF-α or IGF1 treatment. Both, mRNA and miRNA expression profiling was performed. The data-driven integration of target prediction and paired mRNA/miRNA expression profiling data revealed that i) the quantity of predicted miRNA-mRNA relations was reduced, ii) miRNA targets with a function in cell cycle and axon guidance were enriched, iii) differential regulation of anti-differentiation miR-155-5p and miR-29b-3p as well as pro-differentiation miR-335-3p, miR-335-5p, miR-322-3p, and miR-322-5p seemed to be of primary importance during skeletal myoblast differentiation compared to the other miRNAs, iv) the abundance of targets and affected biological processes was miRNA specific, and v) subsets of miRNAs may collectively regulate gene expression. Conclusions Joint analysis of mRNA and miRNA profiling data increased the process-specificity and quality of predicted relations by statistically selecting miRNA-target interactions. Moreover, this study revealed miRNA-specific predominant biological implications in skeletal muscle cell differentiation and in response to TNF-α or IGF1 treatment. Furthermore, myoblast differentiation-associated miRNAs are suggested to collectively regulate gene clusters and targets associated with enriched specific gene ontology terms or pathways. Predicted miRNA functions of this study provide novel insights into defective regulation at the transcriptomic level during myocyte proliferation and differentiation due to inflammatory stimuli.
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Affiliation(s)
- Swanhild U. Meyer
- Physiology Weihenstephan, Technische Universität München, Freising, Germany
- * E-mail:
| | - Steffen Sass
- Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Nikola S. Mueller
- Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Stefan Krebs
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Stefan Bauersachs
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Sebastian Kaiser
- Department of Statistics, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Helmut Blum
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Sabine Krause
- Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Fabian J. Theis
- Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Mathematics, Technische Universität München, Garching, Germany
| | - Michael W. Pfaffl
- Physiology Weihenstephan, Technische Universität München, Freising, Germany
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21
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Benlhabib H, Guo W, Pierce BM, Mendelson CR. The miR-200 family and its targets regulate type II cell differentiation in human fetal lung. J Biol Chem 2015. [PMID: 26203191 DOI: 10.1074/jbc.m114.636068] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Type II cell differentiation and expression of the major surfactant protein, SP-A, in mid-gestation human fetal lung (HFL) are induced by cAMP and inhibited by TGF-β. cAMP induction of SP-A promoter activity is mediated by increased phosphorylation and DNA binding of thyroid transcription factor-1 (TTF-1/Nkx2.1), a master regulator of lung development. To further define mechanisms for developmental induction of surfactant synthesis in HFL, herein, we investigated the potential roles of microRNAs (miRNAs, miRs). To identify and characterize differentially regulated miRNAs in mid-gestation HFL explants during type II pneumocyte differentiation in culture, we performed miRNA microarray of RNA from epithelial cells isolated from mid-gestation HFL explants before and after culture with or without Bt2cAMP. Interestingly, the miR-200 family was significantly up-regulated during type II cell differentiation; miR-200 induction was inversely correlated with expression of known targets, transcription factors ZEB1/2 and TGF-β2. miR-200 antagonists inhibited TTF-1 and surfactant proteins and up-regulated TGF-β2 and ZEB1 expression in type II cells. Overexpression of ZEB1 in type II cells decreased DNA binding of endogenous TTF-1, blocked cAMP stimulation of surfactant proteins, and inhibited miR-200 expression, whereas cAMP markedly inhibited ZEB1/2 and TGF-β. Importantly, overexpression of ZEB1 or miR-200 antagonists in HFL type II cells also inhibited LPCAT1 and ABCA3, enzymes involved in surfactant phospholipid synthesis and trafficking, and blocked lamellar body biogenesis. Our findings suggest that the miR-200 family and ZEB1, which exist in a double-negative feedback loop regulated by TGF-β, serve important roles in the developmental regulation of type II cell differentiation and function in HFL.
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Affiliation(s)
- Houda Benlhabib
- From the Departments of Biochemistry and Obstetrics and Gynecology, North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038
| | - Wei Guo
- From the Departments of Biochemistry and Obstetrics and Gynecology, North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038
| | - Brianne M Pierce
- From the Departments of Biochemistry and Obstetrics and Gynecology, North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038
| | - Carole R Mendelson
- From the Departments of Biochemistry and Obstetrics and Gynecology, North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038
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22
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Mitra R, Lin CC, Eischen CM, Bandyopadhyay S, Zhao Z. Concordant dysregulation of miR-5p and miR-3p arms of the same precursor microRNA may be a mechanism in inducing cell proliferation and tumorigenesis: a lung cancer study. RNA (NEW YORK, N.Y.) 2015; 21:1055-1065. [PMID: 25852169 PMCID: PMC4436660 DOI: 10.1261/rna.048132.114] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 02/11/2015] [Indexed: 05/29/2023]
Abstract
A precursor microRNA (miRNA) has two arms: miR-5p and miR-3p (miR-5p/-3p). Depending on the tissue or cell types, both arms can become functional. However, little is known about their coregulatory mechanisms during the tumorigenic process. Here, by using the large-scale miRNA expression profiles of five cancer types, we revealed that several of miR-5p/-3p arms were concordantly dysregulated in each cancer. To explore possible coregulatory mechanisms of concordantly dysregulated miR-5p/-3p pairs, we developed a robust computational framework and applied it to lung cancer data. The framework deciphers miR-5p/-3p coregulated protein interaction networks critical to lung cancer development. As a novel part in the method, we uniquely applied the second-order partial correlation to minimize false-positive regulations. Using 279 matched miRNA and mRNA expression profiles extracted from tumor and normal lung tissue samples, we identified 17 aberrantly expressed miR-5p/-3p pairs that potentially modulate the gene expression of 35 protein complexes. Functional analyses revealed that these complexes are associated with cancer-related biological processes, suggesting the oncogenic potential of the reported miR-5p/-3p pairs. Specifically, we revealed that the reduced expression of miR-145-5p/-3p pair potentially contributes to elevated expression of genes in the "FOXM1 transcription factor network" pathway, which may consequently lead to uncontrolled cell proliferation. Subsequently, the regulation of miR-145-5p/-3p in the FOXM1signaling pathway was validated by a cohort of 104 matched miRNA and protein (reverse-phase protein array) expression profiles in lung cancer. In summary, our computational framework provides a novel tool to study miR-5p/-3p coregulatory mechanisms in cancer and other diseases.
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Affiliation(s)
- Ramkrishna Mitra
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA
| | - Chen-Ching Lin
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA
| | - Christine M Eischen
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
| | | | - Zhongming Zhao
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA Center for Quantitative Sciences, Vanderbilt University, Nashville, Tennessee 37232, USA
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Bajan S, Hutvagner G. Regulation of miRNA processing and miRNA mediated gene repression in cancer. Microrna 2015; 3:10-7. [PMID: 25069508 PMCID: PMC4260356 DOI: 10.2174/2211536602666140110234046] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/13/2013] [Accepted: 12/20/2013] [Indexed: 12/19/2022]
Abstract
The majority of human protein-coding genes are predicted to be targets of miRNA-mediated post-transcriptional regulation. The widespread influence of miRNAs is illustrated by their essential roles in all biological processes. Regulated miRNA expression is essential for maintaining cellular differentiation; therefore alterations in miRNA expression patterns are associated with several diseases, including various cancers. High-throughput sequencing technologies revealed low level expressing miRNA isoforms, termed isomiRs. IsomiRs may differ in sequence, length, target preference and expression patterns from their parental miRNA and can arise from differences in miRNA biosynthesis, RNA editing, or SNPs inherent to the miRNA gene. The association between isomiR expression and disease progression is largely unknown. Misregulated miRNA expression is thought to contribute to the formation and/or progression of cancer. However, due to the diversity of targeted transcripts, miRNAs can function as both tumor-suppressor genes and oncogenes as defined by cellular context. Despite this, miRNA profiling studies concluded that the differential expression of particular miRNAs in diseased tissue could aid the diagnosis and treatment of some cancers.
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Affiliation(s)
| | - Gyorgy Hutvagner
- Correspondence: Faculty of Engineering and Information Technology, Centre of Health Technology, University of Technology Sydney, Sydney, Australia
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24
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Ulfenborg B, Jurcevic S, Lindlöf A, Klinga-Levan K, Olsson B. miREC: a database of miRNAs involved in the development of endometrial cancer. BMC Res Notes 2015; 8:104. [PMID: 25889518 PMCID: PMC4383082 DOI: 10.1186/s13104-015-1052-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 03/11/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Endometrial cancer (EC) is the most frequently diagnosed gynecological malignancy and the fourth most common cancer diagnosis overall among women. As with many other forms of cancer, it has been shown that certain miRNAs are differentially expressed in EC and these miRNAs are believed to play important roles as regulators of processes involved in the development of the disease. With the rapidly growing number of studies of miRNA expression in EC, there is a need to organize the data, combine the findings from experimental studies of EC with information from various miRNA databases, and make the integrated information easily accessible for the EC research community. FINDINGS The miREC database is an organized collection of data and information about miRNAs shown to be differentially expressed in EC. The database can be used to map connections between miRNAs and their target genes in order to identify specific miRNAs that are potentially important for the development of EC. The aim of the miREC database is to integrate all available information about miRNAs and target genes involved in the development of endometrial cancer, and to provide a comprehensive, up-to-date, and easily accessible source of knowledge regarding the role of miRNAs in the development of EC. Database URL: http://www.mirecdb.org . CONCLUSIONS Several databases have been published that store information about all miRNA targets that have been predicted or experimentally verified to date. It would be a time-consuming task to navigate between these different data sources and literature to gather information about a specific disease, such as endometrial cancer. The miREC database is a specialized data repository that, in addition to miRNA target information, keeps track of the differential expression of genes and miRNAs potentially involved in endometrial cancer development. By providing flexible search functions it becomes easy to search for EC-associated genes and miRNAs from different starting points, such as differential expression and genomic loci (based on genomic aberrations).
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Affiliation(s)
- Benjamin Ulfenborg
- Systems Biology Research Centre - Bioinformatics, University of Skövde, Box 408, 541 28, Skövde, Sweden.
| | - Sanja Jurcevic
- Systems Biology Research Centre - Tumor Biology, University of Skövde, Box 408, 54128, Skövde, Sweden.
| | - Angelica Lindlöf
- Systems Biology Research Centre - Bioinformatics, University of Skövde, Box 408, 541 28, Skövde, Sweden.
| | - Karin Klinga-Levan
- Systems Biology Research Centre - Tumor Biology, University of Skövde, Box 408, 54128, Skövde, Sweden.
| | - Björn Olsson
- Systems Biology Research Centre - Bioinformatics, University of Skövde, Box 408, 541 28, Skövde, Sweden.
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25
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Aure MR, Jernström S, Krohn M, Vollan HKM, Due EU, Rødland E, Kåresen R, Ram P, Lu Y, Mills GB, Sahlberg KK, Børresen-Dale AL, Lingjærde OC, Kristensen VN. Integrated analysis reveals microRNA networks coordinately expressed with key proteins in breast cancer. Genome Med 2015; 7:21. [PMID: 25873999 PMCID: PMC4396592 DOI: 10.1186/s13073-015-0135-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 01/19/2015] [Indexed: 01/20/2023] Open
Abstract
Background The role played by microRNAs in the deregulation of protein expression in breast cancer is only partly understood. To gain insight, the combined effect of microRNA and mRNA expression on protein expression was investigated in three independent data sets. Methods Protein expression was modeled as a multilinear function of powers of mRNA and microRNA expression. The model was first applied to mRNA and protein expression for 105 selected cancer-associated genes and to genome-wide microRNA expression from 283 breast tumors. The model considered both the effect of one microRNA at a time and all microRNAs combined. In the latter case the Lasso penalized regression method was applied to detect the simultaneous effect of multiple microRNAs. Results An interactome map for breast cancer representing all direct and indirect associations between the expression of microRNAs and proteins was derived. A pattern of extensive coordination between microRNA and protein expression in breast cancer emerges, with multiple clusters of microRNAs being associated with multiple clusters of proteins. Results were subsequently validated in two independent breast cancer data sets. A number of the microRNA-protein associations were functionally validated in a breast cancer cell line. Conclusions A comprehensive map is derived for the co-expression in breast cancer of microRNAs and 105 proteins with known roles in cancer, after filtering out the in-cis effect of mRNA expression. The analysis suggests that group action by several microRNAs to deregulate the expression of proteins is a common modus operandi in breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0135-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Miriam Ragle Aure
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway
| | - Sandra Jernström
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway
| | - Marit Krohn
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway
| | - Hans Kristian Moen Vollan
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway ; Department of Oncology, Division of Surgery, Cancer and Transplantation, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway
| | - Eldri U Due
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway
| | - Einar Rødland
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; Centre for Cancer Biomedicine, University of Oslo, Oslo, 0316 Norway ; Department of Computer Science, University of Oslo, Oslo, 0316 Norway
| | - Rolf Kåresen
- Institute of Clinical Medicine, University of Oslo, Oslo, 0316 Norway
| | | | - Prahlad Ram
- Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
| | - Yiling Lu
- Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
| | - Kristine Kleivi Sahlberg
- K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway ; Department of Research, Vestre Viken Hospital Trust, Drammen, 3004 Norway
| | - Anne-Lise Børresen-Dale
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway
| | - Ole Christian Lingjærde
- K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway ; Centre for Cancer Biomedicine, University of Oslo, Oslo, 0316 Norway ; Department of Computer Science, University of Oslo, Oslo, 0316 Norway
| | - Vessela N Kristensen
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310 Norway ; K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316 Norway ; Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Division of Medicine, Akershus University Hospital, Lørenskog, 1478 Norway
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26
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Obermayer B, Levine E. Exploring the miRNA regulatory network using evolutionary correlations. PLoS Comput Biol 2014; 10:e1003860. [PMID: 25299225 PMCID: PMC4191876 DOI: 10.1371/journal.pcbi.1003860] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 08/18/2014] [Indexed: 01/01/2023] Open
Abstract
Post-transcriptional regulation by miRNAs is a widespread and highly conserved phenomenon in metazoans, with several hundreds to thousands of conserved binding sites for each miRNA, and up to two thirds of all genes under miRNA regulation. At the same time, the effect of miRNA regulation on mRNA and protein levels is usually quite modest and associated phenotypes are often weak or subtle. This has given rise to the notion that the highly interconnected miRNA regulatory network exerts its function less through any individual link and more via collective effects that lead to a functional interdependence of network links. We present a Bayesian framework to quantify conservation of miRNA target sites using vertebrate whole-genome alignments. The increased statistical power of our phylogenetic model allows detection of evolutionary correlation in the conservation patterns of site pairs. Such correlations could result from collective functions in the regulatory network. For instance, co-conservation of target site pairs supports a selective benefit of combinatorial regulation by multiple miRNAs. We find that some miRNA families are under pronounced co-targeting constraints, indicating a high connectivity in the regulatory network, while others appear to function in a more isolated way. By analyzing coordinated targeting of different curated gene sets, we observe distinct evolutionary signatures for protein complexes and signaling pathways that could reflect differences in control strategies. Our method is easily scalable to analyze upcoming larger data sets, and readily adaptable to detect high-level selective constraints between other genomic loci. We thus provide a proof-of-principle method to understand regulatory networks from an evolutionary perspective.
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Affiliation(s)
- Benedikt Obermayer
- Systems Biology of Gene Regulatory Elements, Max-Delbrück Center for Molecular Medicine, Berlin, Germany
- Department of Physics and Center for Systems Biology, Harvard University, Cambridge, United Kingdom
- * E-mail: (BO); (EL)
| | - Erel Levine
- Systems Biology of Gene Regulatory Elements, Max-Delbrück Center for Molecular Medicine, Berlin, Germany
- Department of Physics and Center for Systems Biology, Harvard University, Cambridge, United Kingdom
- * E-mail: (BO); (EL)
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27
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Yogev O, Lagos D, Enver T, Boshoff C. Kaposi's sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells. PLoS Pathog 2014; 10:e1004400. [PMID: 25255370 PMCID: PMC4177984 DOI: 10.1371/journal.ppat.1004400] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 08/14/2014] [Indexed: 02/01/2023] Open
Abstract
Altered cell metabolism is inherently connected with pathological conditions including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). KS tumour cells display features of lymphatic endothelial differentiation and in their vast majority are latently infected with KSHV, while a small number are lytically infected, producing virions. Latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, the metabolic properties of KSHV-infected cells closely resemble the metabolic hallmarks of cancer cells. However, how and why KSHV alters host cell metabolism remains poorly understood. Here, we investigated the effect of KSHV infection on the metabolic profile of primary dermal microvascular lymphatic endothelial cells (LEC) and the functional relevance of this effect. We found that the KSHV microRNAs within the oncogenic cluster collaborate to decrease mitochondria biogenesis and to induce aerobic glycolysis in infected cells. KSHV microRNAs expression decreases oxygen consumption, increase lactate secretion and glucose uptake, stabilize HIF1α and decreases mitochondria copy number. Importantly this metabolic shift is important for latency maintenance and provides a growth advantage. Mechanistically we show that KSHV alters host cell energy metabolism through microRNA-mediated down regulation of EGLN2 and HSPA9. Our data suggest that the KSHV microRNAs induce a metabolic transformation by concurrent regulation of two independent pathways; transcriptional reprograming via HIF1 activation and reduction of mitochondria biogenesis through down regulation of the mitochondrial import machinery. These findings implicate viral microRNAs in the regulation of the cellular metabolism and highlight new potential avenues to inhibit viral latency. Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of this neoplasm. The discovery of KSHV and its oncogenic enigmas has enlightened many fields of tumor biology and viral oncogenesis. The metabolic properties of KS significantly differ from those of normal cells and resemble cancer cells in general, but the mechanisms employed by KSHV to alter host cell metabolism are poorly understood. Our work demonstrates that KSHV microRNAs can alter cell metabolism through coherent control of independent pathways, a key feature of microRNA-mediated control of cellular functions. This provides a fresh perspective for how microRNA-encoding pathogens shape a cell's metabolism to create an optimal environment for their survival and/or replication. Indeed, we show that, in the case of KSHV, viral microRNA-driven regulation of metabolism is important for viral latency. These findings will evoke new and exciting approaches to prevent KSHV from establishing latency and later on KS.
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MESH Headings
- Aerobiosis
- Blotting, Western
- Bone Neoplasms/metabolism
- Bone Neoplasms/pathology
- Bone Neoplasms/virology
- Cell Proliferation
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelial Cells/virology
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Endothelium, Vascular/virology
- Energy Metabolism
- Gene Expression Regulation, Viral
- Glucose/metabolism
- Herpesvirus 8, Human/physiology
- Humans
- Lactic Acid/metabolism
- MicroRNAs/genetics
- Mitochondria/metabolism
- Mitochondria/pathology
- Mitochondria/virology
- Osteosarcoma/metabolism
- Osteosarcoma/pathology
- Osteosarcoma/virology
- Oxygen Consumption
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Sarcoma, Kaposi/metabolism
- Sarcoma, Kaposi/pathology
- Sarcoma, Kaposi/virology
- Tumor Cells, Cultured
- Virion/metabolism
- Virus Latency
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Affiliation(s)
- Ohad Yogev
- UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom
- * E-mail:
| | - Dimitris Lagos
- Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom
| | - Tariq Enver
- UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom
| | - Chris Boshoff
- UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom
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28
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Ye Y, Li D, Ouyang D, Deng L, Zhang Y, Ma Y, Li Y. MicroRNA expression in the aging mouse thymus. Gene 2014; 547:218-25. [DOI: 10.1016/j.gene.2014.06.039] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 06/05/2014] [Accepted: 06/19/2014] [Indexed: 01/03/2023]
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29
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Moyret-Lalle C, Ruiz E, Puisieux A. Epithelial-mesenchymal transition transcription factors and miRNAs: “Plastic surgeons” of breast cancer. World J Clin Oncol 2014; 5:311-322. [PMID: 25114847 PMCID: PMC4127603 DOI: 10.5306/wjco.v5.i3.311] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/18/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelial-mesenchymal transition (EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-to-epithelial transition (MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be the preferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT (TFs) and the miRNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and miRNAs, where miRNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of miRNA biogenesis, the ribonuclease type III endonuclease Dicer plays a central role in EMT-TFs/miRNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.
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30
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Afshar AS, Xu J, Goutsias J. Integrative identification of deregulated miRNA/TF-mediated gene regulatory loops and networks in prostate cancer. PLoS One 2014; 9:e100806. [PMID: 24968068 PMCID: PMC4072696 DOI: 10.1371/journal.pone.0100806] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 05/28/2014] [Indexed: 01/07/2023] Open
Abstract
MicroRNAs (miRNAs) have attracted a great deal of attention in biology and medicine. It has been hypothesized that miRNAs interact with transcription factors (TFs) in a coordinated fashion to play key roles in regulating signaling and transcriptional pathways and in achieving robust gene regulation. Here, we propose a novel integrative computational method to infer certain types of deregulated miRNA-mediated regulatory circuits at the transcriptional, post-transcriptional and signaling levels. To reliably predict miRNA-target interactions from mRNA/miRNA expression data, our method collectively utilizes sequence-based miRNA-target predictions obtained from several algorithms, known information about mRNA and miRNA targets of TFs available in existing databases, certain molecular structures identified to be statistically over-represented in gene regulatory networks, available molecular subtyping information, and state-of-the-art statistical techniques to appropriately constrain the underlying analysis. In this way, the method exploits almost every aspect of extractable information in the expression data. We apply our procedure on mRNA/miRNA expression data from prostate tumor and normal samples and detect numerous known and novel miRNA-mediated deregulated loops and networks in prostate cancer. We also demonstrate instances of the results in a number of distinct biological settings, which are known to play crucial roles in prostate and other types of cancer. Our findings show that the proposed computational method can be used to effectively achieve notable insights into the poorly understood molecular mechanisms of miRNA-mediated interactions and dissect their functional roles in cancer in an effort to pave the way for miRNA-based therapeutics in clinical settings.
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Affiliation(s)
- Ali Sobhi Afshar
- Whitaker Biomedical Engineering Institute, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Joseph Xu
- Whitaker Biomedical Engineering Institute, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - John Goutsias
- Whitaker Biomedical Engineering Institute, The Johns Hopkins University, Baltimore, Maryland, United States of America
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31
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Zhu W, Chen YPP. Computational developments in microRNA-regulated protein-protein interactions. BMC SYSTEMS BIOLOGY 2014; 8:14. [PMID: 24507415 PMCID: PMC3922185 DOI: 10.1186/1752-0509-8-14] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 01/20/2014] [Indexed: 01/12/2023]
Abstract
Protein-protein interaction (PPI) is one of the most important functional components of a living cell. Recently, researchers have been interested in investigating the correlation between PPI and microRNA, which has been found to be a regulator at the post-transcriptional level. Studies on miRNA-regulated PPI networks will not only facilitate an understanding of the fine tuning role that miRNAs play in PPI networks, but will also provide potential candidates for tumor diagnosis. This review describes basic studies on the miRNA-regulated PPI network in the way of bioinformatics which includes constructing a miRNA-target protein network, describing the features of miRNA-regulated PPI networks and overviewing previous findings based on analysing miRNA-regulated PPI network features.
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Affiliation(s)
| | - Yi-Ping Phoebe Chen
- Department of Computer Science and Computer Engineering, La Trobe University, Melbourne, Australia.
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32
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Alshalalfa M, D. Bader G, Bismar TA, Alhajj R. Coordinate microRNA-mediated regulation of protein complexes in prostate cancer. PLoS One 2013; 8:e84261. [PMID: 24391925 PMCID: PMC3877262 DOI: 10.1371/journal.pone.0084261] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 11/21/2013] [Indexed: 11/18/2022] Open
Abstract
MicroRNAs are a class of small non-coding regulatory RNA molecules that regulate mRNAs post-transcriptionally. Recent evidence has shown that miRNAs target entire functionally related proteins such as protein complexes and biological pathways. However, characterizing the influence of miRNAs on genes whose encoded proteins are part of protein complexes has not been studied in the context of disease. We propose an entropy-based framework to identify miRNA-mediated dysregulation of functionally related proteins during prostate cancer progression. The proposed framework uses experimentally verified miRNA-target interactions, functionally related proteins and expression data to identify miRNA-influenced protein complexes in prostate cancer, and identify genes that are dysregulated as a result. The framework constructs correlation matrixes between functionally related proteins and miRNAs that have targets in the complex, and assesses the changes in the Shannon entropy of the modules across different stages of prostate cancer. Results reveal that SMAD4 and HDAC containing protein complexes are highly affected and disrupted by miRNAs, particularly miRNA-1 and miRNA-16. Using biological pathways to define functionally related proteins reveals that NF-kB-, RAS-, and Syndecan-mediated pathways are dysregulated due to miRNA-1- and miRNA-16-mediated regulation. These results suggest that miRNA-1 and miRNA-16 are important master regulators of miRNA-mediated regulation in prostate cancer. Moreover, results reveal that miRNAs with high-influence on the disrupted protein complexes are diagnostic and prognostic biomarker candidates for prostate cancer progression. The observation of miRNA-mediated protein complex regulation and miRNA-mediated pathway regulation, with partial experimental verification from previous studies, demonstrates that our framework is a promising approach for the identification of novel miRNAs and protein complexes related to disease progression.
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Affiliation(s)
- Mohammed Alshalalfa
- Department of Computer Science, University of Calgary, Calgary, Alberta, Canada
- Biotechnology Research Centre, Palestine Polytechnic University, Hebron, Palestine
- * E-mail:
| | - Gary D. Bader
- The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada and the Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Tarek A. Bismar
- Departments of Pathology, Oncology and Molecular Biology and Biochemistry, Faculty of Medicine, University of Calgary, Alberta, Canada
| | - Reda Alhajj
- Department of Computer Science, University of Calgary, Calgary, Alberta, Canada
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Le HS, Bar-Joseph Z. Integrating sequence, expression and interaction data to determine condition-specific miRNA regulation. Bioinformatics 2013; 29:i89-97. [PMID: 23813013 PMCID: PMC3694655 DOI: 10.1093/bioinformatics/btt231] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Motivation: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. MiRNAs were shown to play an important role in development and disease, and accurately determining the networks regulated by these miRNAs in a specific condition is of great interest. Early work on miRNA target prediction has focused on using static sequence information. More recently, researchers have combined sequence and expression data to identify such targets in various conditions. Results: We developed the Protein Interaction-based MicroRNA Modules (PIMiM), a regression-based probabilistic method that integrates sequence, expression and interaction data to identify modules of mRNAs controlled by small sets of miRNAs. We formulate an optimization problem and develop a learning framework to determine the module regulation and membership. Applying PIMiM to cancer data, we show that by adding protein interaction data and modeling cooperative regulation of mRNAs by a small number of miRNAs, PIMiM can accurately identify both miRNA and their targets improving on previous methods. We next used PIMiM to jointly analyze a number of different types of cancers and identified both common and cancer-type-specific miRNA regulators. Contact:zivbj@cs.cmu.edu Supplementary information:Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Hai-Son Le
- Machine Learning Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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34
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Gorini G, Nunez YO, Mayfield RD. Integration of miRNA and protein profiling reveals coordinated neuroadaptations in the alcohol-dependent mouse brain. PLoS One 2013; 8:e82565. [PMID: 24358208 PMCID: PMC3865091 DOI: 10.1371/journal.pone.0082565] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 10/24/2013] [Indexed: 12/12/2022] Open
Abstract
The molecular mechanisms underlying alcohol dependence involve different neurochemical systems and are brain region-dependent. Chronic Intermittent Ethanol (CIE) procedure, combined with a Two-Bottle Choice voluntary drinking paradigm, represents one of the best available animal models for alcohol dependence and relapse drinking. MicroRNAs, master regulators of the cellular transcriptome and proteome, can regulate their targets in a cooperative, combinatorial fashion, ensuring fine tuning and control over a large number of cellular functions. We analyzed cortex and midbrain microRNA expression levels using an integrative approach to combine and relate data to previous protein profiling from the same CIE-subjected samples, and examined the significance of the data in terms of relative contribution to alcohol consumption and dependence. MicroRNA levels were significantly altered in CIE-exposed dependent mice compared with their non-dependent controls. More importantly, our integrative analysis identified modules of coexpressed microRNAs that were highly correlated with CIE effects and predicted target genes encoding differentially expressed proteins. Coexpressed CIE-relevant proteins, in turn, were often negatively correlated with specific microRNA modules. Our results provide evidence that microRNA-orchestrated translational imbalances are driving the behavioral transition from alcohol consumption to dependence. This study represents the first attempt to combine ex vivo microRNA and protein expression on a global scale from the same mammalian brain samples. The integrative systems approach used here will improve our understanding of brain adaptive changes in response to drug abuse and suggests the potential therapeutic use of microRNAs as tools to prevent or compensate multiple neuroadaptations underlying addictive behavior.
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Affiliation(s)
- Giorgio Gorini
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America
- * E-mail:
| | - Yury O. Nunez
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America
| | - R. Dayne Mayfield
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America
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35
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Alshalalfa M. miRNA regulation in the context of functional protein networks: principles and applications. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2013; 6:189-99. [PMID: 24532562 DOI: 10.1002/wsbm.1251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding endogenous regulatory RNAs that fine-tune gene expression in a wide range of biological processes and diseases. miRNAs exert their function by targeting mRNAs to trigger their degradation or inhibit protein translation. The proteins encoded by the genes targeted by miRNAs may act as key components of cellular networks, thus the use of biological molecular network information for the purposes of elucidating the role of miRNAs in molecular disease mechanism is a key objective in systems biomedicine. The crosstalk layer between miRNA-target networks and functional protein is rich sources of information to explore the function of miRNAs at the system level. Characterizing the influence of miRNAs in the context of the target (protein interactors of the target) is in the early stages with potential to help better understand how miRNAs function within the cellular networks. In this article, the latest research on the cross-talk between miRNAs and protein networks, particularly physical protein interactions and gene regulatory networks is summarized. This article also covers recent research on understanding the biology of miRNAs at the system level and defines principles of miRNA regulation of protein and gene regulatory networks. The second part of the article highlights the promise of considering the protein context of the miRNA target when searching for functional miRNA-target interactions. Some of the applications of integrating protein networks with miRNA-targets that have clinical and functional utility are described.
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Affiliation(s)
- Mohammed Alshalalfa
- Department of Computer Science, University of Calgary, Calgary, Alberta, Canada
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Wang L, Tian WD, Xu X, Nie B, Lu J, Liu X, Zhang B, Dong Q, Sunwoo JB, Li G, Li XP. Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells. Cancer 2013; 120:363-72. [PMID: 24190575 DOI: 10.1002/cncr.28418] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND The Epstein-Barr virus (EBV)-encoded EB nuclear antigen 1 (EBNA1) protein is required for maintenance and transmission of the viral episome in EBV-infected cells. The objective of this study was to investigate the role of EBNA1 protein in nasopharyngeal carcinoma (NPC). METHODS Tissue samples from 48 patients with NPC and 12 patients with chronic nasopharyngitis were subjected to immunohistochemical analysis of EBNA1 expression. EBNA1 combinational DNA was used to overexpress EBNA1 protein in NPC cell lines to assess tumor cell epithelial-mesenchymal transition (EMT), colony formation, migration and invasion, and gene expression. RESULTS EBNA1 protein was highly expressed in NPC tissue specimens, and its expression was associated with NPC lymph node metastasis. EBNA1 expression affected NPC cell morphology and the expression of EMT markers in vitro. Furthermore, overexpression of EBNA1 inhibited the expression of microRNA 200a (miR-200a) and miR-200b and, in turn, up-regulated expression of their target genes, zinc finger E-box binding homeobox 1 ( ZEB1) and ZEB2, which are well known mediators of EMT. In addition, EBNA1-regulated miR-200a and miR-200b expression was mediated by transforming growth factor-β1. CONCLUSIONS The current findings provided novel insight into the vital role of EBNA1 in manipulating a molecular switch of EMT in EBV-positive NPC cells.
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Affiliation(s)
- Lu Wang
- Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Chavali S, Bruhn S, Tiemann K, Sætrom P, Barrenäs F, Saito T, Kanduri K, Wang H, Benson M. MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases. RNA (NEW YORK, N.Y.) 2013; 19:1552-1562. [PMID: 24062574 PMCID: PMC3851722 DOI: 10.1261/rna.038414.113] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 08/20/2013] [Indexed: 06/02/2023]
Abstract
MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.
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Affiliation(s)
- Sreenivas Chavali
- MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom
| | - Sören Bruhn
- The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping, SE-58185, Sweden
| | - Katrin Tiemann
- The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping, SE-58185, Sweden
| | - Pål Sætrom
- Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway
| | - Fredrik Barrenäs
- The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping, SE-58185, Sweden
| | - Takaya Saito
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NO-7491, Norway
| | - Kartiek Kanduri
- The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, SE 40530, Sweden
| | - Hui Wang
- The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping, SE-58185, Sweden
- The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, SE 40530, Sweden
| | - Mikael Benson
- The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping, SE-58185, Sweden
- Pediatric Allergy Unit, Queen Silvia Children's Hospital, Gothenburg, SE 41685, Sweden
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Singhal R, Bard JE, Nowak NJ, Buck MJ, Kandel ES. FOXO1 regulates expression of a microRNA cluster on X chromosome. Aging (Albany NY) 2013; 5:347-56. [PMID: 23748164 PMCID: PMC3701110 DOI: 10.18632/aging.100558] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Phosphoinositol-3-kinase (PI3K) pathway is a crucial modulator of many physiological and pathophysiological phenomena, including aging, diabetes and cancer. Protein kinase Akt, a downstream effector of PI3K, controls a plethora of cellular functions, including gene transcription. A key mechanism connecting Akt activity to changes in gene expression is inhibitory phosphorylation of FOXO family of transcription factors. Accordingly, altered expression of FOXO targets may account for many biological consequences of PI3K/Akt signaling. While the previous efforts focused on FOXO-dependent regulation of protein-coding genes, non-coding RNA genes have emerged as equally important targets of many transcription factors. Therefore, we utilized a regulated form of FOXO1 to profile FOXO1-dependent changes in miRNA expression in human cells. Both microarray hybridization and next-generation sequencing revealed changes in the products of a miRNA cluster on X chromosome. Rapid induction of these miRNAs occurred independently of de novo protein synthesis. Furthermore, inhibition of PI3K in cancer cell lines caused derepression of these miRNAs, as would be expected for FOXO-regulated genes. Members of the major oncogenic cascades are significantly overrepresented among the predicted targets of the miRNAs, consistent with tumor-suppressive role of FOXO1. The discovered miRNAs represent new candidate mediators of FOXO1 functions and possible biomarkers of its activity.
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Affiliation(s)
- Ruchi Singhal
- Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC L3-318, Buffalo, NY 14263, USA
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Alshalalfa M, Alhajj R. Using context-specific effect of miRNAs to identify functional associations between miRNAs and gene signatures. BMC Bioinformatics 2013; 14 Suppl 12:S1. [PMID: 24267745 PMCID: PMC3848857 DOI: 10.1186/1471-2105-14-s12-s1] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND MicroRNAs are a class of short regulatory RNAs that act as post-transcriptional fine-tune regulators of a large host of genes that play key roles in many cellular processes and signaling pathways. A useful step for understanding their functional role is characterizing their influence on the protein context of the targets. Using miRNA context-specific influence as a functional signature is promising to identify functional associations between miRNAs and other gene signatures, and thus advance our understanding of miRNA mode of action. RESULTS In the current study we utilized the power of regularized regression models to construct functional associations between gene signatures. Genes that are influenced by miRNAs directly(computational miRNA target prediction) or indirectly (protein partners of direct targets) are defined as functional miRNA gene signature. The combined direct and indirect miRNA influence is defined as context-specific effects of miRNAs, and is used to identify regulatory effects of miRNAs on curated gene signatures. Elastic-net regression was used to build functional associations between context-specific effect of miRNAs and other gene signatures (disease, pathway signatures) by identifying miRNAs whose targets are enriched in gene lists. As a proof of concept, elastic-net regression was applied on lists of genes downregulated upon pre-miRNA transfection, and successfully identified the treated miRNA. This model was then extended to construct functional relationships between miRNAs and disease and pathway gene lists. Integrating context-specific effects of miRNAs on a protein network reveals more significant miRNA enrichment in prostate gene signatures compared to miRNA direct targets. The model identified novel list of miRNAs that are associated with prostate clinical variables. CONCLUSIONS Elastic-net regression is used as a model to construct functional associations between miRNA signatures and other gene signatures. Defining miRNA context-specific functional gene signature by integrating the downstream effect of miRNAs demonstrates better performance compared to the miRNA signature alone (direct targets). miRNA functional signatures can greatly facilitate miRNA research to uncover new functional associations between miRNAs and diseases, drugs or pathways.
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Lemons D, Maurya MR, Subramaniam S, Mercola M. Developing microRNA screening as a functional genomics tool for disease research. Front Physiol 2013; 4:223. [PMID: 23986717 PMCID: PMC3753477 DOI: 10.3389/fphys.2013.00223] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 08/02/2013] [Indexed: 02/04/2023] Open
Abstract
Originally discovered as regulators of developmental timing in C. elegans, microRNAs (miRNAs) have emerged as modulators of nearly every cellular process, from normal development to pathogenesis. With the advent of whole genome libraries of miRNA mimics suitable for high throughput screening, it is possible to comprehensively evaluate the function of each member of the miRNAome in cell-based assays. Since the relatively few microRNAs in the genome are thought to directly regulate a large portion of the proteome, miRNAome screening, coupled with the identification of the regulated proteins, might be a powerful new approach to gaining insight into complex biological processes.
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Affiliation(s)
- Derek Lemons
- Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA ; Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute La Jolla, CA, USA
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Sass S, Buettner F, Mueller NS, Theis FJ. A modular framework for gene set analysis integrating multilevel omics data. Nucleic Acids Res 2013; 41:9622-33. [PMID: 23975194 PMCID: PMC3834824 DOI: 10.1093/nar/gkt752] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Modern high-throughput methods allow the investigation of biological functions across multiple ‘omics’ levels. Levels include mRNA and protein expression profiling as well as additional knowledge on, for example, DNA methylation and microRNA regulation. The reason for this interest in multi-omics is that actual cellular responses to different conditions are best explained mechanistically when taking all omics levels into account. To map gene products to their biological functions, public ontologies like Gene Ontology are commonly used. Many methods have been developed to identify terms in an ontology, overrepresented within a set of genes. However, these methods are not able to appropriately deal with any combination of several data types. Here, we propose a new method to analyse integrated data across multiple omics-levels to simultaneously assess their biological meaning. We developed a model-based Bayesian method for inferring interpretable term probabilities in a modular framework. Our Multi-level ONtology Analysis (MONA) algorithm performed significantly better than conventional analyses of individual levels and yields best results even for sophisticated models including mRNA fine-tuning by microRNAs. The MONA framework is flexible enough to allow for different underlying regulatory motifs or ontologies. It is ready-to-use for applied researchers and is available as a standalone application from http://icb.helmholtz-muenchen.de/mona.
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Affiliation(s)
- Steffen Sass
- Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany and Department of Mathematics, Technische Universität München, Boltzmannstraße 3, 85747 Garching, Germany
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Stankiewicz TR, Schroeder EK, Kelsey NA, Bouchard RJ, Linseman DA. C-terminal binding proteins are essential pro-survival factors that undergo caspase-dependent downregulation during neuronal apoptosis. Mol Cell Neurosci 2013; 56:322-332. [PMID: 23859824 DOI: 10.1016/j.mcn.2013.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 06/25/2013] [Accepted: 07/08/2013] [Indexed: 12/20/2022] Open
Abstract
C-terminal binding proteins (CtBPs) are transcriptional co-repressors that are subject to proteasome-dependent downregulation during apoptosis. Alternative mechanisms that regulate CtBP expression are currently under investigation and the role of CtBPs in neuronal survival is largely unexplored. Here, we show that CtBPs are downregulated in cerebellar granule neurons (CGNs) induced to undergo apoptosis by a variety of stressors. Moreover, antisense-mediated downregulation of CtBP1 is sufficient to cause CGN apoptosis. Similarly, the CtBP inhibitor, 4-methylthio-2-oxobutyric acid, induces expression of the CtBP target Noxa and causes actinomycin-sensitive CGN apoptosis. Unexpectedly, we found that the mechanism of CtBP downregulation in CGNs undergoing apoptosis varies in a stimulus-specific manner involving either the proteasome or caspases. In the case of CGNs deprived of depolarizing potassium (5K apoptotic condition), caspases appear to play a dominant role in CtBP downregulation. However, incubation in 5K does not enhance the kinetics of CtBP1 degradation and recombinant CtBP1 is not cleaved in vitro by caspase-3. In addition, 5K has no significant effect on CtBP transcript expression. Finally, mouse embryonic stem cells display caspase-dependent downregulation of CtBP1 following exposure to staurosporine, an effect that is not observed in DGCR8 knockout cells which are deficient in miRNA processing. These data identify caspase-dependent downregulation of CtBPs as an alternative mechanism to the proteasome for regulation of these transcriptional co-repressors in neurons undergoing apoptosis. Moreover, caspases appear to regulate CtBP expression indirectly, at a post-transcriptional level, and via a mechanism that is dependent upon miRNA processing. We conclude that CtBPs are essential pro-survival proteins in neurons and their downregulation contributes significantly to neuronal apoptosis via the de-repression of pro-apoptotic genes.
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Affiliation(s)
- Trisha R Stankiewicz
- Research Service, Veterans Affairs Medical Center, Denver, Colorado, 80220, USA.,Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado, 80208, USA
| | - Emily K Schroeder
- Research Service, Veterans Affairs Medical Center, Denver, Colorado, 80220, USA
| | - Natalie A Kelsey
- Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado, 80208, USA
| | - Ron J Bouchard
- Research Service, Veterans Affairs Medical Center, Denver, Colorado, 80220, USA
| | - Daniel A Linseman
- Research Service, Veterans Affairs Medical Center, Denver, Colorado, 80220, USA.,Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado, 80208, USA.,Division of Clinical Pharmacology and Toxicology, Department of Medicine and Neuroscience Program, University of Colorado School of Medicine, Aurora, Colorado, 80045, USA
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Complex-forming proteins escape the robust regulations of miRNA in human. FEBS Lett 2013; 587:2284-7. [PMID: 23756149 DOI: 10.1016/j.febslet.2013.05.062] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 05/21/2013] [Accepted: 05/29/2013] [Indexed: 12/14/2022]
Abstract
Most proteins carry out their functions by participating in protein complexes. Recently, miRNAs were identified as promising post-transcriptional regulators that influence a large proportion of genes in higher eukaryotes. We aim to understand the role of miRNAs in the regulation of human proteins that are present in protein complexes. Here, we show that robust regulation by miRNA is absent in human complex-forming proteins. Moreover, the numbers of miRNA hits cannot direct the evolutionary fate of complex-forming proteins independently. However, the duplicated complex-forming proteins having a severe effect on organismal fitness are profoundly targeted by miRNA, probably to reduce the chances of dosage imbalance.
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Qabaja A, Alshalalfa M, Bismar TA, Alhajj R. Protein network-based Lasso regression model for the construction of disease-miRNA functional interactions. EURASIP JOURNAL ON BIOINFORMATICS & SYSTEMS BIOLOGY 2013; 2013:3. [PMID: 23339438 PMCID: PMC3606436 DOI: 10.1186/1687-4153-2013-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 10/29/2012] [Indexed: 12/26/2022]
Abstract
Background There is a growing body of evidence associating microRNAs (miRNAs) with human diseases. MiRNAs are new key players in the disease paradigm demonstrating roles in several human diseases. The functional association between miRNAs and diseases remains largely unclear and far from complete. With the advent of high-throughput functional genomics techniques that infer genes and biological pathways dysregulted in diseases, it is now possible to infer functional association between diseases and biological molecules by integrating disparate biological information. Results Here, we first used Lasso regression model to identify miRNAs associated with disease signature as a proof of concept. Then we proposed an integrated approach that uses disease-gene associations from microarray experiments and text mining, and miRNA-gene association from computational predictions and protein networks to build functional associations network between miRNAs and diseases. The findings of the proposed model were validated against gold standard datasets using ROC analysis and results were promising (AUC=0.81). Our protein network-based approach discovered 19 new functional associations between prostate cancer and miRNAs. The new 19 associations were validated using miRNA expression data and clinical profiles and showed to act as diagnostic and prognostic prostate biomarkers. The proposed integrated approach allowed us to reconstruct functional associations between miRNAs and human diseases and uncovered functional roles of newly discovered miRNAs. Conclusions Lasso regression was used to find associations between diseases and miRNAs using their gene signature. Defining miRNA gene signature by integrating the downstream effect of miRNAs demonstrated better performance than the miRNA signature alone. Integrating biological networks and multiple data to define miRNA and disease gene signature demonstrated high performance to uncover new functional associations between miRNAs and diseases.
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Affiliation(s)
- Ala Qabaja
- Department of Computer Science, University of Calgary, Calgary, Alberta, Canada.
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A systematic screen reveals MicroRNA clusters that significantly regulate four major signaling pathways. PLoS One 2012; 7:e48474. [PMID: 23144891 PMCID: PMC3493556 DOI: 10.1371/journal.pone.0048474] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 09/26/2012] [Indexed: 11/19/2022] Open
Abstract
MicroRNAs (miRNAs) are encoded in the genome as individual miRNA genes or as gene clusters transcribed as polycistronic units. About 50% of all miRNAs are estimated to be co-expressed with neighboring miRNAs. Recent studies have begun to illuminate the importance of the clustering of miRNAs from an evolutionary, as well as a functional standpoint. Many miRNA clusters coordinately regulate multiple members of cellular signaling pathways or protein interaction networks. This cooperative method of targeting could produce effects on an overall process that are much more dramatic than the smaller effects often associated with regulation by an individual miRNA. In this study, we screened 366 human miRNA minigenes to determine their effects on the major signaling pathways culminating in AP-1, NF-κB, c-Myc, or p53 transcriptional activity. By stratifying these data into miRNA clusters, this systematic screen provides experimental evidence for the combined effects of clustered miRNAs on these signaling pathways. We also verify p53 as a direct target of miR-200a. This study is the first to provide a panoramic view of miRNA clusters' effects on cellular pathways.
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Alshalalfa M, Bader GD, Goldenberg A, Morris Q, Alhajj R. Detecting microRNAs of high influence on protein functional interaction networks: a prostate cancer case study. BMC SYSTEMS BIOLOGY 2012; 6:112. [PMID: 22929553 PMCID: PMC3490713 DOI: 10.1186/1752-0509-6-112] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 08/14/2012] [Indexed: 11/10/2022]
Abstract
BACKGROUND The use of biological molecular network information for diagnostic and prognostic purposes and elucidation of molecular disease mechanism is a key objective in systems biomedicine. The network of regulatory miRNA-target and functional protein interactions is a rich source of information to elucidate the function and the prognostic value of miRNAs in cancer. The objective of this study is to identify miRNAs that have high influence on target protein complexes in prostate cancer as a case study. This could provide biomarkers or therapeutic targets relevant for prostate cancer treatment. RESULTS Our findings demonstrate that a miRNA's functional role can be explained by its target protein connectivity within a physical and functional interaction network. To detect miRNAs with high influence on target protein modules, we integrated miRNA and mRNA expression profiles with a sequence based miRNA-target network and human functional and physical protein interactions (FPI). miRNAs with high influence on target protein complexes play a role in prostate cancer progression and are promising diagnostic or prognostic biomarkers. We uncovered several miRNA-regulated protein modules which were enriched in focal adhesion and prostate cancer genes. Several miRNAs such as miR-96, miR-182, and miR-143 demonstrated high influence on their target protein complexes and could explain most of the gene expression changes in our analyzed prostate cancer data set. CONCLUSIONS We describe a novel method to identify active miRNA-target modules relevant to prostate cancer progression and outcome. miRNAs with high influence on protein networks are valuable biomarkers that can be used in clinical investigations for prostate cancer treatment.
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Sen K, Ghosh TC. Evolutionary conservation and disease gene association of the human genes composing pseudogenes. Gene 2012; 501:164-70. [PMID: 22521745 DOI: 10.1016/j.gene.2012.04.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Revised: 02/09/2012] [Accepted: 04/05/2012] [Indexed: 01/16/2023]
Abstract
Pseudogenes, the 'genomic fossils' present portrayal of evolutionary history of human genome. The human genes configuring pseudogenes are also now coming forth as important resources in the study of human protein evolution. In this communication, we explored evolutionary conservation of the genes forming pseudogenes over the genes lacking any pseudogene and delving deeper, we probed an evolutionary rate difference between the disease genes in the two groups. We illustrated this differential evolutionary pattern by gene expressivity, number of regulatory miRNA targeting per gene, abundance of protein complex forming genes and lesser percentage of protein intrinsic disorderness. Furthermore, pseudogenes are observed to harbor sequence variations, over their entirety, those become degenerative disease-causing mutations though the disease involvement of their progenitors is still unexplored. Here, we unveiled an immense association of disease genes in the genes casting pseudogenes in human. We interpreted the issue by disease associated miRNA targeting, genes containing polymorphisms in miRNA target sites, abundance of genes having disease causing non-synonymous mutations, disease gene specific network properties, presence of genes having repeat regions, affluence of dosage sensitive genes and the presence of intrinsically unstructured protein regions.
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Affiliation(s)
- Kamalika Sen
- Bioinformatics Centre, Bose Institute, P 1/12, C.I.T. Scheme VII M, Kolkata 700 054, India.
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Gennarino VA, D'Angelo G, Dharmalingam G, Fernandez S, Russolillo G, Sanges R, Mutarelli M, Belcastro V, Ballabio A, Verde P, Sardiello M, Banfi S. Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res 2012; 22:1163-72. [PMID: 22345618 PMCID: PMC3371699 DOI: 10.1101/gr.130435.111] [Citation(s) in RCA: 148] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) and transcription factors control eukaryotic cell proliferation, differentiation, and metabolism through their specific gene regulatory networks. However, differently from transcription factors, our understanding of the processes regulated by miRNAs is currently limited. Here, we introduce gene network analysis as a new means for gaining insight into miRNA biology. A systematic analysis of all human miRNAs based on Co-expression Meta-analysis of miRNA Targets (CoMeTa) assigns high-resolution biological functions to miRNAs and provides a comprehensive, genome-scale analysis of human miRNA regulatory networks. Moreover, gene cotargeting analyses show that miRNAs synergistically regulate cohorts of genes that participate in similar processes. We experimentally validate the CoMeTa procedure through focusing on three poorly characterized miRNAs, miR-519d/190/340, which CoMeTa predicts to be associated with the TGFβ pathway. Using lung adenocarcinoma A549 cells as a model system, we show that miR-519d and miR-190 inhibit, while miR-340 enhances TGFβ signaling and its effects on cell proliferation, morphology, and scattering. Based on these findings, we formalize and propose co-expression analysis as a general paradigm for second-generation procedures to recognize bona fide targets and infer biological roles and network communities of miRNAs.
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Goh WWB, Oikawa H, Sng JCG, Sergot M, Wong L. The role of miRNAs in complex formation and control. ACTA ACUST UNITED AC 2011; 28:453-6. [PMID: 22180412 DOI: 10.1093/bioinformatics/btr693] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
UNLABELLED microRibonucleic acid (miRNAs) are small regulatory molecules that act by mRNA degradation or via translational repression. Although many miRNAs are ubiquitously expressed, a small subset have differential expression patterns that may give rise to tissue-specific complexes. MOTIVATION This work studies gene targeting patterns amongst miRNAs with differential expression profiles, and links this to control and regulation of protein complexes. RESULTS We find that, when a pair of miRNAs are not expressed in the same tissues, there is a higher tendency for them to target the direct partners of the same hub proteins. At the same time, they also avoid targeting the same set of hub-spokes. Moreover, the complexes corresponding to these hub-spokes tend to be specific and nonoverlapping. This suggests that the effect of miRNAs on the formation of complexes is specific.
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