LINEAGE DETERMINATION IN MUSCLE

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): The combination of microarray analysis of gene expression and molecular studies of transcription-factor activity are beginning to reveal the circuitry of gene expression networks. We have shown that the myogenic transcription factor, MyoD, functions in an instructive chromatin context and directly regulates genes that are expressed throughout the myogenic program, achieving promoter-specific regulation of its own binding and activity through a feed-forward mechanism. This gives us the opportunity to deconstruct the myogenic program into discrete molecular regulatory phases, similar to the cellular compartments identified in hematopoietic cell development. The broad and long-term objective of the parent application is to apply the knowledge we have gained from our studies of gene regulation in myogenesis to identify the molecular defect(s) in the differentiation program of rhabdomyosarcomas. We have used our model systems of MyoD-mediated regulation of gene expression to demonstrate that a dynamic balance between MyoD and MSC arrest the rhabdomyosarcoma cells in an unstable transitional state that normally occurs during myoblast growth and differentiation. This leads to a new broad hypothesis regarding transitional cell states: The regulative growth phase is an unstable state maintained by a dynamic balance between antagonistic factors that bind an overlapping network of genes, such as MyoD and MSC in skeletal myogenesis. The goal of this Revision application to the parent is to identify the systems wide regulatory interactions between MyoD and MSC. This will provide new insight into the network mechanisms that regulate transitional states in mammalian cell differentiation.