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Integrated approaches to miRNAs target definition: time-series analysis in an osteosarcoma differentiative model.

ABSTRACT: microRNAs (miRs) are small non-coding RNAs involved in the fine regulation of several cellular processes by inhibiting their target genes at post-transcriptional level. Osteosarcoma (OS) is a tumor thought to be related to a molecular blockade of the normal process of osteoblast differentiation. The current paper explores temporal transcriptional modifications comparing an osteosarcoma cell line, Saos-2, and clones stably transfected with CD99, a molecule which was found to drive OS cells to terminally differentiate.Parental cell line and CD99 transfectants were cultured up to 14 days in differentiating medium. In this setting, OS cells were profiled by gene and miRNA expression arrays. Integration of gene and miRNA profiling was performed by both sequence complementarity and expression correlation. Further enrichment and network analyses were carried out to focus on the modulated pathways and on the interactions between transcriptome and miRNome. To track the temporal transcriptional modification, a PCA analysis with differentiated human MSC was performed.We identified a strong (about 80 %) gene down-modulation where reversion towards the osteoblast-like phenotype matches significant enrichment in TGFbeta signaling players like AKT1 and SMADs. In parallel, we observed the modulation of several cancer-related microRNAs like miR-34a, miR-26b or miR-378. To decipher their impact on the modified transcriptional program in CD99 cells, we correlated gene and microRNA time-series data miR-34a, in particular, was found to regulate a distinct subnetwork of genes with respect to the rest of the other differentially expressed miRs and it appeared to be the main mediator of several TGFbeta signaling genes at initial and middle phases of differentiation. Integration studies further highlighted the involvement of TGFbeta pathway in the differentiation of OS cells towards osteoblasts and its regulation by microRNAs.These data underline that the expression of miR-34a and down-modulation of TGFbeta signaling emerge as pivotal events to drive CD99-mediated reversal of malignancy and activation of differentiation in OS cells. Our results describe crucial and specific interacting actors providing and supporting their relevance as potential targets for therapeutic differentiative strategies.

SUBMITTER: Grilli A

PROVIDER: S-EPMC4486310 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Integrated approaches to miRNAs target definition: time-series analysis in an osteosarcoma differentiative model.

Grilli A A Sciandra M M Terracciano M M Picci P P Scotlandi K K

BMC medical genomics 20150630

<h4>Background</h4>microRNAs (miRs) are small non-coding RNAs involved in the fine regulation of several cellular processes by inhibiting their target genes at post-transcriptional level. Osteosarcoma (OS) is a tumor thought to be related to a molecular blockade of the normal process of osteoblast differentiation. The current paper explores temporal transcriptional modifications comparing an osteosarcoma cell line, Saos-2, and clones stably transfected with CD99, a molecule which was found to dr ...[more]

PMID: 26123714

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Project description:In this paper, we introduce a novel model selection approach to time series forecasting. For linear stationary processes, such as AR processes, the direction of time is independent of the model parameters. By combining theoretical principles of time-reversibility in time series with conventional modeling approaches such as information criteria, we construct a criterion that employs the backwards prediction (backcast) as a proxy for the forecast. Hereby, we aim to adopt a theoretically grounded, data-driven approach to model selection. The novel criterion is named the backwards validated information criterion (BVIC). The BVIC identifies suitable models by trading off a measure of goodness-of-fit and a models ability to predict backwards. We test the performance of the BVIC by conducting experiments on synthetic and real data. In each experiment, the BVIC is examined in contrast to conventionally employed criteria. Our experimental results suggest that the BVIC has comparable performance as conventional information criteria. Specifically, in most of the experiments performed, we did not find statistically significant differences between the forecast error of the BVIC under certain parameterizations and that of the different information criteria. Nonetheless, it is worth emphasizing that the BVIC guarantees are established by design where the model order penalization term depends on strong mathematical properties of time-reversible time series forecasting properties and a finite data assessment. In particular, the penalization term is replaced by a weighted trade-off between functional dimensions pertaining to forecasting.That said, we observed that the BVIC recovered more accurately the real order of the underlying process than the other criteria, which rely on a static penalization of the model order. Lastly, leveraging the latter property we perform the assessment of the order model (or, memory) of time series pertaining to epileptic seizures recorded using electrocorticographic data. Our results provide converging evidence that the order of the model increases during the epileptic events.

Dataset Information

Integrated approaches to miRNAs target definition: time-series analysis in an osteosarcoma differentiative model.

Publications

Integrated approaches to miRNAs target definition: time-series analysis in an osteosarcoma differentiative model.

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