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Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.

ABSTRACT: Cancer pain remains a major challenge and there is an urgent demand for the development of specific mechanism-based therapies. Various diseases are associated with unique signatures of expression of microRNAs (miRNAs), which reveal deep insights into disease pathology. Using a comprehensive approach combining genome-wide miRNA screening, molecular and in silico analyses with behavioural approaches in a clinically relevant model of metastatic bone-cancer pain in mice, we now show that tumour-induced conditions are associated with a marked dysregulation of 57 miRNAs in sensory neurons corresponding to tumour-affected areas. By establishing protocols for interference with disease-induced miRNA dysregulation in peripheral sensory neurons in vivo, we functionally validate six dysregulated miRNAs as significant modulators of tumour-associated hypersensitivity. In silico analyses revealed that their predicted targets include key pain-related genes and we identified Clcn3, a gene encoding a chloride channel, as a key miRNA target in sensory neurons, which is functionally important in tumour-induced nociceptive hypersensitivity in vivo. Our results provide new insights into endogenous gene regulatory mechanisms in cancer pain and open up attractive and viable therapeutic options.

SUBMITTER: Bali KK

PROVIDER: S-EPMC3840489 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.

Bali Kiran Kumar KK Selvaraj Deepitha D Satagopam Venkata P VP Lu Jianning J Schneider Reinhard R Kuner Rohini R

EMBO molecular medicine 20131018 11

Cancer pain remains a major challenge and there is an urgent demand for the development of specific mechanism-based therapies. Various diseases are associated with unique signatures of expression of microRNAs (miRNAs), which reveal deep insights into disease pathology. Using a comprehensive approach combining genome-wide miRNA screening, molecular and in silico analyses with behavioural approaches in a clinically relevant model of metastatic bone-cancer pain in mice, we now show that tumour-indu ...[more]

PMID: 24039159

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Project description:BackgroundCalmodulin (CaM) is a major calcium sensor in all eukaryotes. It binds calcium and modulates the activity of a wide range of downstream proteins in response to calcium signals. However, little is known about the CaM gene family in Solanaceous species, including the economically important species, tomato (Solanum lycopersicum), and the gene silencing model plant, Nicotiana benthamiana. Moreover, the potential function of CaM in plant disease resistance remains largely unclear.ResultsWe performed genome-wide identification of CaM gene families in Solanaceous species. Employing bioinformatics approaches, multiple full-length CaM genes were identified from tomato, N. benthamiana and potato (S. tuberosum) genomes, with tomato having 6 CaM genes, N. benthamiana having 7 CaM genes, and potato having 4 CaM genes. Sequence comparison analyses showed that three tomato genes, SlCaM3/4/5, two potato genes StCaM2/3, and two sets of N. benthamiana genes, NbCaM1/2/3/4 and NbCaM5/6, encode identical CaM proteins, yet the genes contain different intron/exon organization and are located on different chromosomes. Further sequence comparisons and gene structural and phylogenetic analyses reveal that Solanaceous species gained a new group of CaM genes during evolution. These new CaM genes are unusual in that they contain three introns in contrast to only a single intron typical of known CaM genes in plants. The tomato CaM (SlCaM) genes were found to be expressed in all organs. Prediction of cis-acting elements in 5' upstream sequences and expression analyses demonstrated that SlCaM genes have potential to be highly responsive to a variety of biotic and abiotic stimuli. Additionally, silencing of SlCaM2 and SlCaM6 altered expression of a set of signaling and defense-related genes and resulted in significantly lower resistance to Tobacco rattle virus and the oomycete pathogen, Pythium aphanidermatum.ConclusionsThe CaM gene families in the Solanaceous species tomato, N. benthamiana and potato were identified through a genome-wide analysis. All three plant species harbor a small set of genes that encode identical CaM proteins, which may manifest a strategy of plants to retain redundancy or enhanced quantitative gene function. In addition, Solanaceous species have evolved one new group of CaM genes during evolution. CaM genes play important roles in plant disease resistance to a variety of pathogens.

Project description:RNA silencing is mediated through RNA interference (RNAi) pathway gene families, i.e., Dicer-Like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) and their cis-acting regulatory elements. The RNAi pathway is also directly connected with the post-transcriptional gene silencing (PTGS) mechanism, and the pathway controls eukaryotic gene regulation during growth, development, and stress response. Nevertheless, genome-wide identification of RNAi pathway gene families such as DCL, AGO, and RDR and their regulatory network analyses related to transcription factors have not been studied in many fruit crop species, including banana (Musa acuminata). In this study, we studied in silico genome-wide identification and characterization of DCL, AGO, and RDR genes in bananas thoroughly via integrated bioinformatics approaches. A genome-wide analysis identified 3 MaDCL, 13 MaAGO, and 5 MaRDR candidate genes based on multiple sequence alignment and phylogenetic tree related to the RNAi pathway in banana genomes. These genes correspond to the Arabidopsis thaliana RNAi silencing genes. The analysis of the conserved domain, motif, and gene structure (exon-intron numbers) for MaDCL, MaAGO, and MaRDR genes showed higher homogeneity within the same gene family. The Gene Ontology (GO) enrichment analysis exhibited that the identified RNAi genes could be involved in RNA silencing and associated metabolic pathways. A number of important transcription factors (TFs), e.g., ERF, Dof, C2H2, TCP, GATA and MIKC_MADS families, were identified by network and sub-network analyses between TFs and candidate RNAi gene families. Furthermore, the cis-acting regulatory elements related to light-responsive (LR), stress-responsive (SR), hormone-responsive (HR), and other activities (OT) functions were identified in candidate MaDCL, MaAGO, and MaRDR genes. These genome-wide analyses of these RNAi gene families provide valuable information related to RNA silencing, which would shed light on further characterization of RNAi genes, their regulatory elements, and functional roles, which might be helpful for banana improvement in the breeding program.

Project description:RNA interference (RNAi) regulates a variety of eukaryotic gene expressions that are engaged in response to stress, growth, and the conservation of genomic stability during developmental phases. It is also intimately connected to the post-transcriptional gene silencing (PTGS) process and chromatin modification levels. The entire process of RNA interference (RNAi) pathway gene families mediates RNA silencing. The main factors of RNA silencing are the Dicer-Like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) gene families. To the best of our knowledge, genome-wide identification of RNAi gene families like DCL, AGO, and RDR in sunflower (Helianthus annuus) has not yet been studied despite being discovered in some species. So, the goal of this study is to find the RNAi gene families like DCL, AGO, and RDR in sunflower based on bioinformatics approaches. Therefore, we accomplished an inclusive in silico investigation for genome-wide identification of RNAi pathway gene families DCL, AGO, and RDR through bioinformatics approaches such as (sequence homogeneity, phylogenetic relationship, gene structure, chromosomal localization, PPIs, GO, sub-cellular localization). In this study, we have identified five DCL (HaDCLs), fifteen AGO (HaAGOs), and ten RDR (HaRDRs) in the sunflower genome database corresponding to the RNAi genes of model plant Arabidopsis thaliana based on genome-wide analysis and a phylogenetic method. The analysis of the gene structure that contains exon-intron numbers, conserved domain, and motif composition analyses for all HaDCL, HaAGO, and HaRDR gene families indicated almost homogeneity among the same gene family. The protein-protein interaction (PPI) network analysis illustrated that there exists interconnection among identified three gene families. The analysis of the Gene Ontology (GO) enrichment showed that the detected genes directly contribute to the RNA gene-silencing and were involved in crucial pathways. It was observed that the cis-acting regulatory components connected to the identified genes were shown to be responsive to hormone, light, stress, and other functions. That was found in HaDCL, HaAGO, and HaRDR genes associated with the development and growth of plants. Finally, we are able to provide some essential information about the components of sunflower RNA silencing through our genome-wide comparison and integrated bioinformatics analysis, which open the door for further research into the functional mechanisms of the identified genes and their regulatory elements.

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Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.

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Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.

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