Limits...
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).

Show MeSH

Related in: MedlinePlus

Model of OS cell proliferation.The picture illustrates the proposed model of OS cell proliferation co-regulated by miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC. These regulators control mainly components of the NFKB- and RB1-pathway and of focal adhesion processes. Primary microRNA targets are rectangular and secondary targets are ellipse shaped. Red marks up-regulated genes in proliferative active OS cell lines and green indicates down-regulated genes. White nodes represent genes not DE in OS cell proliferation. Solid and dashed arrows illustrate direct and indirect functional associations, respectively. RB1 is shaded in red to indicate that it is no member of the global networks.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3757060&req=5

pcbi-1003210-g006: Model of OS cell proliferation.The picture illustrates the proposed model of OS cell proliferation co-regulated by miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC. These regulators control mainly components of the NFKB- and RB1-pathway and of focal adhesion processes. Primary microRNA targets are rectangular and secondary targets are ellipse shaped. Red marks up-regulated genes in proliferative active OS cell lines and green indicates down-regulated genes. White nodes represent genes not DE in OS cell proliferation. Solid and dashed arrows illustrate direct and indirect functional associations, respectively. RB1 is shaded in red to indicate that it is no member of the global networks.

Mentions: After examining and discussing the structural and functional aspects of the co-regulatory networks, we integrated the main results of the present study into a potential model of OS cell proliferation (Figure 6). The focus of the model is on microRNA and TF co-regulation of the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC.


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)

Model of OS cell proliferation.The picture illustrates the proposed model of OS cell proliferation co-regulated by miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC. These regulators control mainly components of the NFKB- and RB1-pathway and of focal adhesion processes. Primary microRNA targets are rectangular and secondary targets are ellipse shaped. Red marks up-regulated genes in proliferative active OS cell lines and green indicates down-regulated genes. White nodes represent genes not DE in OS cell proliferation. Solid and dashed arrows illustrate direct and indirect functional associations, respectively. RB1 is shaded in red to indicate that it is no member of the global networks.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003210-g006: Model of OS cell proliferation.The picture illustrates the proposed model of OS cell proliferation co-regulated by miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC. These regulators control mainly components of the NFKB- and RB1-pathway and of focal adhesion processes. Primary microRNA targets are rectangular and secondary targets are ellipse shaped. Red marks up-regulated genes in proliferative active OS cell lines and green indicates down-regulated genes. White nodes represent genes not DE in OS cell proliferation. Solid and dashed arrows illustrate direct and indirect functional associations, respectively. RB1 is shaded in red to indicate that it is no member of the global networks.
Mentions: After examining and discussing the structural and functional aspects of the co-regulatory networks, we integrated the main results of the present study into a potential model of OS cell proliferation (Figure 6). The focus of the model is on microRNA and TF co-regulation of the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC.

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