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scientific background: osteosarcoma is a primary bone tumor affecting mainly children and considered as a complex tumor due to the important genomic rearrangement. growing evidences point toward a role of histone variants in its development. establishment and characterization of mouse models of osteosarcoma will be critical to elucidate the molecular bases of this disease. description of the project: histone variants are key regulators of transcription and genomic stability. alterations in the histone variant expression and their genome-wide distribution patterns are hallmarks for different cancer types. histone variant h3.3a and h3.3b gene products are mutated (k36m mutation in h3.3b and g34w or g34l mutated in h3.3a) in human bone cancer. in this project, we would like to elucidate the role of histone variants in osteosarcoma development. toward this goal, we have generated a mouse model of osteosarcoma. we have started the generation of an osteosarcoma mouse model in which either h3.3 or h2az will be specifically invalidated. these mice will used to characterize the expression pattern of histone variants and their chaperones during normal and osteosarcoma development. our hypothesis is that distinct histone variants and their chaperones would exhibit altered (over- or down-regulation) pattern of expression and, or mutations in osteosarcoma. this would lead, in turn, to severe changes in the chromatin landscape and consequently, to perturbations of the expression pattern of numerous genes, a situation very often observed in cancer cells. to test this, we will use the state-of-the-art biochemistry, molecular and cellular biology as well as proteomic and genomic approaches (at genome-wide level) combined with mouse genetics and structural studies. results: this project will allow us to understand the role of histone variants in the malignant process, notably, their potential role in osteosarcoma development.