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MiR-206 integrates multiple components of differentiation pathways to control the transition from growth to differentiation in rhabdomyosarcoma cells (miRNA)

ABSTRACT: Background: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance existed between various inhibitory transcription factors and MyoD activity that kept rhabdomyosarcomas trapped in a proliferative state. Methods: Potential myogenic co-factors identified by analysis of high-throughput sequencing of chromatin immunoprecipitation experiments in normal myogenic cells were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. Results: Modulation of the transcription factors RUNX1 and ZNF238, factors with poorly delineated roles in myogenic development, can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. Conclusions: These findings suggest that nested feed-forward circuits that proceed from MyoD, to RUNX1, to ZNF238, and finally to miR-206 function in both rhabdomyosarcomas as well as normal myogenesis to control the decision point of proliferation versus differentiation.

ORGANISM(S): Mus musculus Pan troglodytes Saguinus labiatus Canis lupus familiaris Betapolyomavirus macacae Murid gammaherpesvirus 4 Physcomitrium patens Ateles geoffroyi Macaca nemestrina Ovis aries Apis mellifera Human betaherpesvirus 5 Drosophila melanogaster Oryza sativa Macacine gammaherpesvirus 4 Arabidopsis thaliana Xenopus laevis Gallid alphaherpesvirus 2 Glycine max human gammaherpesvirus 4 Saccharum officinarum Gorilla gorilla Medicago truncatula Bos taurus Human gammaherpesvirus 8 Rattus norvegicus Takifugu rubripes Pan paniscus Schmidtea mediterranea Homo sapiens Monodelphis domestica Pongo pygmaeus Caenorhabditis elegans Populus trichocarpa Drosophila pseudoobscura Zea mays Xenopus tropicalis Lagothrix lagotricha Danio rerio Lemur catta Sus scrofa Caenorhabditis briggsae Gallus gallus Anopheles gambiae Tetraodon nigroviridis Bombyx mori Sorghum bicolor Macaca mulatta

PROVIDER: GSE35606 | GEO | 2012/04/02

SECONDARY ACCESSION(S): PRJNA155883

REPOSITORIES: GEO

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Project description:Background: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance existed between various inhibitory transcription factors and MyoD activity that kept rhabdomyosarcomas trapped in a proliferative state. Methods: Potential myogenic co-factors identified by analysis of high-throughput sequencing of chromatin immunoprecipitation experiments in normal myogenic cells were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. Results: Modulation of the transcription factors RUNX1 and ZNF238, factors with poorly delineated roles in myogenic development, can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. Conclusions: These findings suggest that nested feed-forward circuits that proceed from MyoD, to RUNX1, to ZNF238, and finally to miR-206 function in both rhabdomyosarcomas as well as normal myogenesis to control the decision point of proliferation versus differentiation. Total RNA samples were collected from human RD cells transduced with lentivirus carrying RUNX1, RP58 (ZNF238), miR-206 or GFP (three biological replicates each) and allowed to differentiate for 72 hours.

Project description:Background: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance existed between various inhibitory transcription factors and MyoD activity that kept rhabdomyosarcomas trapped in a proliferative state. Methods: Potential myogenic co-factors identified by analysis of high-throughput sequencing of chromatin immunoprecipitation experiments in normal myogenic cells were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. Results: Modulation of the transcription factors RUNX1 and ZNF238, factors with poorly delineated roles in myogenic development, can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. Conclusions: These findings suggest that nested feed-forward circuits that proceed from MyoD, to RUNX1, to ZNF238, and finally to miR-206 function in both rhabdomyosarcomas as well as normal myogenesis to control the decision point of proliferation versus differentiation. Two biologically independent sets of RD cells were transduced with either MD~E or empty vector pCLBabe retroviruses. After RNA extraction pairs of samples (MD~E versus pCLBabe) were hybridized to arrays, incorporating both dye-swap and technical replicates (i.e. 1 comparison x 2 dye-swaps x 2 biological replicates x 2 technical replicates = 8 arrays)

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MiR-206 integrates multiple components of differentiation pathways to control the transition from growth to differentiation in rhabdomyosarcoma cells (miRNA)

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