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How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation.

Poos K, Smida J, Nathrath M, Maugg D, Baumhoer D, Korsching E - PLoS Comput. Biol. (2013)

Bottom Line: These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network.We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks.This study illustrates the benefit of systems biological approaches in the analysis of complex diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioinformatics, University of Münster, Münster, Germany.

ABSTRACT
Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.de/co_networks.html).

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Related in: MedlinePlus

Workflow.The figure illustrates the procedure of the present study determining microRNA and TF co-regulation in OS cell proliferation.
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pcbi-1003210-g001: Workflow.The figure illustrates the procedure of the present study determining microRNA and TF co-regulation in OS cell proliferation.

Mentions: In this study, we joined different data sources to analyze the contribution of microRNA and TF co-regulatory 3-node and 4-node motifs to the proliferative activity of OS cells. First, we divided seven OS cell lines into high and low proliferation groups by performing proliferation assays. Expression analysis based on these groups yielded differentially expressed (DE) microRNAs and mRNAs. Second, high efficacy microRNA target genes were obtained by integrating computational predicted targets with DE mRNAs. Only microRNAs with significantly enriched target genes were considered in the analysis. Third, microRNA target genes were clustered according to their functional similarity to explore their distinct biological processes. Fourth, transcription factor binding site (TFBS) information was added to assemble 3-node and 4-node motifs of non-random microRNA and TF co-regulator pairs. Fifth, the resulting 3-node and 4-node motifs were merged to form microRNA and TF co-regulatory networks to examine the coordinated regulation of microRNAs and TFs (Figure 1).


How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation.

Poos K, Smida J, Nathrath M, Maugg D, Baumhoer D, Korsching E - PLoS Comput. Biol. (2013)

Workflow.The figure illustrates the procedure of the present study determining microRNA and TF co-regulation in OS cell proliferation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757060&req=5

pcbi-1003210-g001: Workflow.The figure illustrates the procedure of the present study determining microRNA and TF co-regulation in OS cell proliferation.
Mentions: In this study, we joined different data sources to analyze the contribution of microRNA and TF co-regulatory 3-node and 4-node motifs to the proliferative activity of OS cells. First, we divided seven OS cell lines into high and low proliferation groups by performing proliferation assays. Expression analysis based on these groups yielded differentially expressed (DE) microRNAs and mRNAs. Second, high efficacy microRNA target genes were obtained by integrating computational predicted targets with DE mRNAs. Only microRNAs with significantly enriched target genes were considered in the analysis. Third, microRNA target genes were clustered according to their functional similarity to explore their distinct biological processes. Fourth, transcription factor binding site (TFBS) information was added to assemble 3-node and 4-node motifs of non-random microRNA and TF co-regulator pairs. Fifth, the resulting 3-node and 4-node motifs were merged to form microRNA and TF co-regulatory networks to examine the coordinated regulation of microRNAs and TFs (Figure 1).

Bottom Line: These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network.We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks.This study illustrates the benefit of systems biological approaches in the analysis of complex diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioinformatics, University of Münster, Münster, Germany.

ABSTRACT
Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.de/co_networks.html).

Show MeSH
Related in: MedlinePlus