The development of non-coding RNA ontology

Identification of non-coding RNAs (ncRNAs) has been significantly improved over the past decade. On the other hand, semantic annotation of ncRNA data is facing critical challenges due to the lack of a comprehensive ontology to serve as common data elements and data exchange standards in the field. We developed the Non-Coding RNA Ontology (NCRO) to handle this situation. By providing a formally defined ncRNA controlled vocabulary, the NCRO aims to fill a specific and highly needed niche in semantic annotation of large amounts of ncRNA biological and clinical data

MMpred: functional miRNA – mRNA interaction analyses by miRNA expression prediction

Background: MicroRNA (miRNA) directed gene repression is an important mechanism of posttranscriptional regulation. Comprehensive analyses of how microRNA influence biological processes requires paired miRNA-mRNA expression datasets. However, a review of both GEO and ArrayExpress repositories revealed few such datasets, which was in stark contrast to the large number of messenger RNA (mRNA) only datasets. It is of interest that numerous primary miRNAs (precursors of microRNA) are known to be co-expressed with coding genes (host genes). Results: We developed a miRNA-mRNA interaction analyses pipeline. The proposed solution is based on two miRNA expression prediction methods – a scaling function and a linear model. Additionally, miRNA-mRNA anticorrelation analyses are used to determine the most probable miRNA gene targets (i.e. the differentially expressed genes under the influence of up- or down-regulated microRNA). Both the consistency and accuracy of the prediction method is ensured by the application of stringent statistical methods. Finally, the predicted targets are subjected to functional enrichment analyses including GO, KEGG and DO, to better understand the predicted interactions. Conclusions: The MMpred pipeline requires only mRNA expression data as input and is independent of third party miRNA target prediction methods. The method passed extensive numerical validation based on the binding energy between the mature miRNA and 3’ UTR region of the target gene. We report that MMpred is capable of generating results similar to that obtained using paired datasets. For the reported test cases we generated consistent output and predicted biological relationships that will help formulate further testable hypotheses

A domain ontology for the non-coding RNA field

Identification of non-coding RNAs (ncRNAs) has been significantly enhanced due to the rapid advancement in sequencing technologies. On the other hand, semantic annotation of ncRNA data lag behind their identification, and there is a great need to effectively integrate discovery from relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a precisely defined ncRNA controlled vocabulary, which can fill a specific and highly needed niche in unification of ncRNA biology

miRDB: An online database for prediction of functional microRNA targets

MicroRNAs (miRNAs) are small noncoding RNAs that act as master regulators in many biological processes. miRNAs function mainly by downregulating the expression of their gene targets. Thus, accurate prediction of miRNA targets is critical for characterization of miRNA functions. To this end, we have developed an online database, miRDB, for miRNA target prediction and functional annotations. Recently, we have performed major updates for miRDB. Specifically, by employing an improved algorithm for miRNA target prediction, we now present updated transcriptome-wide target prediction data in miRDB, including 3.5 million predicted targets regulated by 7000 miRNAs in five species. Further, we have implemented the new prediction algorithm into a web server, allowing custom target prediction with user-provided sequences. Another new database feature is the prediction of cell-specific miRNA targets. miRDB now hosts the expression profiles of over 1000 cell lines and presents target prediction data that are tailored for specific cell models. At last, a new web query interface has been added to miRDB for prediction of miRNA functions by integrative analysis of target prediction and Gene Ontology data. All data in miRDB are freely accessible at http://mirdb.org

HIV-1 gp120 influences the expression of microRNAs in human monocyte-derived dendritic cells via STAT3 activation

Background: MicroRNAs (miRs) are an abundant class of small non-coding RNAs (~22 nt) that reprogram gene ex- pression by targeting mRNA degradation and translational disruption. An emerging concept implicates miR coup- ling with transcription factors in myeloid cell development and function, thus contributing to host defense and inflammation. The important role that these molecules play in the pathogenesis of HIV-1 is only now emerging. Results: We provide evidence that exposure of monocyte-derived dendritic cells (MDDCs) to recombinant HIV-1 R5 gp120, but not to CCR5 natural ligand CCL4, influences the expression of a panel of miRs (i.e., miR-21, miR-155 and miR-181b) regulated by STAT3 and potentially targeting genes belonging to the STAT3 signaling pathway. The blockage of gp120-induced STAT3 activation impairs gp120 capacity to modulate the expression level of above mentioned miRs. Predictive analysis of miR putative targets emphasizes that these miRs share common target genes. Furthermore, gene ontology and pathway enrichment analysis outline that these genes mainly belong to biological processes related to regulation of transcription, in a complex network of interactions involving pathways relevant to HIV-DC interaction. Conclusions: Overall, these results point to gp120-triggered modulation of miR expression via STAT3 activation as a novel molecular mechanism exploited by HIV-1 to affect DC biology and thus modulate the immune response through complex regulatory loops involving, at the same time, miRs and transcription factors

Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced micro- RNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these prodifferentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.Comment: 45 pages 5 figure

The Non-Coding RNA Ontology : a comprehensive resource for the unification of non-coding RNA biology

In recent years, sequencing technologies have enabled the identification of a wide range of non-coding RNAs (ncRNAs). Unfortunately, annotation and integration of ncRNA data has lagged behind their identification. Given the large quantity of information being obtained in this area, there emerges an urgent need to integrate what is being discovered by a broad range of relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a systematically structured and precisely defined controlled vocabulary for the domain of ncRNAs, thereby facilitating the discovery, curation, analysis, exchange, and reasoning of data about structures of ncRNAs, their molecular and cellular functions, and their impacts upon phenotypes. The goal of NCRO is to serve as a common resource for annotations of diverse research in a way that will significantly enhance integrative and comparative analysis of the myriad resources currently housed in disparate sources. It is our belief that the NCRO ontology can perform an important role in the comprehensive unification of ncRNA biology and, indeed, fill a critical gap in both the Open Biological and Biomedical Ontologies (OBO) Library and the National Center for Biomedical Ontology (NCBO) BioPortal. Our initial focus is on the ontological representation of small regulatory ncRNAs, which we see as the first step in providing a resource for the annotation of data about all forms of ncRNAs. The NCRO ontology is free and open to all users

Could the Anti-Chaperone VER155008 Replace Temozolomide for Glioma Treatment

Cancer inducible molecular chaperone HSP90 is of great importance as an anticancer target. Proteomic analysis showed that inhibiting HSP90 by the geldanamycin derivative, 17-AAG elevated the expression of the co-chaperone Hsp70. In this study we used HSP90 selective inhibitor 17-AAG and HSP70/90 dual inhibitor, VER155008 (VER) in U87-MG glioma cells. miRNAs microarray technology was used to evaluate the efficacy of these inhibitory drugs compared with temozolomide (TMZ), used as a standard treatment for glioma. Microarrays data identified 154 differentially expressed miRNAs using stringent or unstringent parameters. 16 miRNAs were overlapped between treatments, 13 upregulated and one downregulated miRNA were overlapped between TMZ and VER. The miRNA target prediction software was used for these overlapped miRNAs and identified 6 of the 13 upregulated miRNAs target methyltransferase genes. The IC50, together with Akt and HSP70 and 90 protein level data favour VER and TMZ to 17-AAG, however due to the selectivity of VER to cancer cells as a potent antichaperon, it may be more favourable to the standard TMZ