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The role of the rhabdoid tumor suppressor hSNF5/INI1 in cell differentiation


Malignant rhabdoid tumour (MRT) are highly aggressive malignant neoplasms of childhood. MRTs show great phenotypic variability in their tissue localisation and differentiation. This phenotypic diversity contrasts with a strong genetic homogeneity characterised by biallelic inactivation of hSNF5/INI1; a subunit of the SWI/SNF chromatin remodelling complex.

This phenotypic variability means that it is unclear in which type of cells MRTs arise. The aim of this proposal is to elucidate how hSNF5/INI1 affects the differentiation of MRTs with a view to identifying an MRT progenitor cell and to examine the role and molecular mechanism of hSNF5/INI1 in various key differentiation programmes.

Microarray expression analyses will be conducted comparing the transcription profiles of MRT lacking hSNF5/INI1 and of MRT cells manipulated to re-express hSNF5/INI1 with these of a variety of normal tissues and immature progenitor cells. In vitro differentiation experiments with MRT cell lines expressing a conditional version of h SNF5/INI1 will enable us to investigate the differentiation potentials of MRT cells from various origins (brain, epithelial, soft tissue).

Furthermore, the requirement for hSNF5/INI1 in well-documented models of cell differentiation (PC12, 3T3L1, C2C12, mesenchymal stem cells) will be evaluated by specifically silencing hSNF5/INI1.

These experiments will be combined with CHip on chip experiments (Chromatin Immunoprecipitation followed by microarray profiling) investigating the promoters bound by hSNF5/INI1 and temporal analysis of the gene expression profile of MRT cells following hSNF5/INI1 activation, this project should contribute to a better understanding of the cellular pathways controlled by hSNF5/INI1 and altered in MRT.

Overall, the project should contribute to a better understanding of both MRT tumourigenesis and the role of chromatin remodelling in cell differentiation.

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