CoGemiR: A comparative genomics microRNA database

BACKGROUND: MicroRNAs are small highly conserved non-coding RNAs which play an important role in regulating gene expression by binding the 3'UTR of target mRNAs. The majority of microRNAs are localized within other transcriptional units (host genes) and are co-expressed with them, which strongly suggests that microRNAs and corresponding host genes use the same promoter and other expression control elements. The remaining fraction of microRNAs is intergenic and is endowed with an independent regulatory region. A number of databases have already been developed to collect information about microRNAs but none of them allow an easy exploration of microRNA genomic organization across evolution. RESULTS: CoGemiR is a publicly available microRNA-centered database whose aim is to offer an overview of the genomic organization of microRNAs and of its extent of conservation during evolution in different metazoan species. The database collects information on genomic location, conservation and expression data of both known and newly predicted microRNAs and displays the data by privileging a comparative point of view. The database also includes a microRNA prediction pipeline to annotate microRNAs in recently sequenced genomes. This information is easily accessible via web through a user-friendly query page. The CoGemiR database is available at http://cogemir.tigem.it/ CONCLUSION: The knowledge of the genomic organization of microRNAs can provide useful information to understand their biology. In order to have a comparative genomics overview of microRNAs genomic organization, we developed CoGemiR. To achieve this goal, we both collected and integrated data from pre-existing databases and generated new ones, such as the identification in several species of a number of previously unannotated microRNAs. For a more effective use of this data, we developed a user-friendly web interface that simply shows how a microRNA genomic context is related in different species

Androgen receptor, PARP signaling, and tumor microenvironment: the ‘perfect triad’ in prostate cancer?

Aberrations in the homologous recombination repair (HRR) pathway in prostate cancer (PCa) provide a unique opportunity to develop therapeutic strategies that take advantage of the reduced tumor ability to repair DNA damage. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have been shown to prolong the survival of PCa patients with HRR defects, particularly in those with Breast Cancer type 1 susceptibility protein/Breast Cancer type 2 susceptibility protein alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple preclinical and clinical studies are addressing potential synergies between PARPi and androgen receptor signaling inhibitors, and these strategies are also being evaluated in combination with other drugs such as immune checkpoint inhibitors. However, the effectiveness of these combining therapies could be hindered by multiple mechanisms of resistance, including also the role played by the immunosuppressive tumor microenvironment. In this review, we summarize the use of PARPi in PCa and the potential synergies with different molecular pathways. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi, expanding the use of genomic tests, and optimizing combination therapies

MicroRNA target prediction by expression analysis of host genes

MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression by inducing RNA cleavage or translational inhibition. Most human miRNAs are intragenic and are transcribed as part of their hosting transcription units. We hypothesized that the expression profiles of miRNA host genes and of their targets are inversely correlated and devised a novel procedure, HOCTAR (host gene oppositely correlated targets), which ranks predicted miRNA target genes based on their anti-correlated expression behavior relative to their respective miRNA host genes. HOCTAR is the first tool for systematic miRNA target prediction that utilizes the same set of microarray experiments to monitor the expression of both miRNAs (through their host genes) and candidate targets. We applied the procedure to 178 human intragenic miRNAs and found that it performs better than currently available prediction softwares in pinpointing previously validated miRNA targets. The high-scoring HOCTAR predicted targets were enriched in Gene Ontology categories, which were consistent with previously published data, as in the case of miR-106b and miR-93. By means of overexpression and loss-of-function assays, we also demonstrated that HOCTAR is efficient in predicting novel miRNA targets and we identified, by microarray and qRT-PCR procedures, 34 and 28 novel targets for miR-26b and miR-98, respectively. Overall, we believe that the use of HOCTAR significantly reduces the number of candidate miRNA targets to be tested compared to the procedures based solely on target sequence recognition. Finally, our data further confirm that miRNAs have a significant impact on the mRNA levels of most of their targets

Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases

Endothelin-1 (ET-1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET-1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET-1 in the presence or absence of an overnight pre-treatment with either ET(A) or ET(B) selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen-activated protein kinases (MAPK). ET-1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL-6/IL-11 release into cell culture supernatants. All these effects were inhibited by the selective ET(A) antagonist BQ-123, but not by the specific ET(B) antagonist BQ-788. The stimulatory influence of ET-1 on IL-11, but not on IL-6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET-1 exerts a profibrogenic action via an ET(A) receptor-dependent, MAPK-mediated induction of IL-11 release and cell proliferation

HOCTAR database: A unique resource for microRNA target prediction

microRNAs (miRNAs) are the most abundant class of small RNAs in mammals. They play an important role in regulation of gene expression by inducing mRNA cleavage or translational inhibition. Each miRNA targets an average of 100–200 genes by binding, preferentially, to their 3′ UTRs by means of partial sequence complementarity. Most miRNAs are localized within transcriptional units, termed host genes, and show similar expression behavior with respect to their corresponding host genes. Considering the impact of miRNA in the regulation of gene expression and their involvement in a growing number of human disorders, it is vital to develop sensitive computational approaches able to identify miRNA target genes. The HOCTAR database (db) is a publicly available resource collecting ranked list of predicted target genes for 290 intragenic miRNAs annotated in human. HOCTARdb is a unique resource that integrates miRNA target prediction genes and transcriptomic data to score putative miRNA targets looking at the expression behavior of their host genes. We demonstrated, by testing 135 known validated target genes (either at the translational or transcriptional level) for different miRNAs, that the miRNA target prediction lists present in HOCTARdb are highly reliable. Moreover, HOCTARdb associates biological roles to each miRNA-controlled transcriptional network by means of Gene Ontology analysis. This information is easily accessible through a user-friendly query page. The HOCTARdb is available at http://hoctar.tigem.it/. We believe that a detailed relationship between miRNAs and their target genes and a constant update of the information contained in HOCTARdb will provide an extremely valuable resource to assist the researcher in the discovery of miRNA target genes

ELM server: A new resource for investigating short functional sites in modular eukaryotic proteins

Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein-protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more

ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins

Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein–protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more