View source for Cellular Network Based Identification of Master Regulators of Physiological and Oncogenic Processes

By Andrea Califano, Columbia University

'''Feb 17, 2009'''

CNLS Conference room.

:The identification of genes acting synergistically as master regulators of physiologic and pathologic cellular phenotypes is a key open problem in systems biology. Here we use a molecular interaction based approach to identify the repertoire of transcription factors (TFs) of a master regulatory module responsible for synergistic activation of a physiologic and tumor-specific signatures. Specifically, we used the ARACNe and the Master Regulator Analysis algorithms to infer regulatory interactions in Human B cells that control formation of Germinal Centers and to identify genes responsible for initiating and maintaining the mesenchymal phenotype of Glioblastoma Multiforme (GBM), previously associated with the poorest disease prognosis. Expression of mesenchymal genes is a hallmark of aggressiveness but the upstream regulators of the signature are unknown. Starting from the unbiased analysis of all TFs, we identify a highly interconnected module of six TFs jointly regulating >75% of the genes in the signature. Two TFs (Stat3 and C/EBPb), in particular, display features of initiators and master regulators of module activity. Ectopic co-expression of these master TFs in murine neural stem cells activates expression of the mesenchymal signature and is highly tumorigenic in vivo. Conversely, co-silencing of the TFs in human glioma cells leads to collapse of the mesenchymal signature and reduction of tumor aggressiveness.

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