To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote the formation of specific cell lineages. Typically, this involves activation of genes that are transcriptionally silent and that are likely incorporated into repressive chromatin structure. Evidence supports the idea that differentiation specific transcriptional regulators and enzymes that remodel or alter chromatin structure cooperate to render genomic DNA more accessible to the transcriptional machinery. SWI/SNF enzymes remodel nucleosome structure in an ATP dependent manner and facilitate transcription factor function in vitro and in vivo. Components of these enzymes are essential for embryonic development and some act as tumor suppressors. Additionally, SWI/SNF enzymes interact with other known tumor suppressors and are implicated in cell cycle control. Thus these enzymes are broadly required for normal cell function and for differentiation and development, and their misregulation is implicated in tumor formation. Skeletal muscle differentiation has long been a model for studying fundamental principles of tissue-specific gene expression and differentiation. The SWI/SNF chromatin remodeling enzymes play essential roles in these processes. This project will focus on the mechanisms by which different kinases and phosphatases involved in signaling pathways regulate the phosphorylation and function of SWI/SNF chromatin remodeling enzyme subunits. Modulation of kinase and phosphatase activities and mutation of modified amino acids in targeted subunit proteins will be the primary approaches to determining mechanisms by which phosphorylation of SWI/SNF enzyme subunits control gene expression and differentiation. The work will provide new paradigms for understanding how signaling molecules converge on chromatin to regulate tissue differentiation and development.
Our proposed studies address how sigaling molecules converge on chromatin to regulate chromatin remodeling, tissue-specific gene expression and tissue differentiation. Using skeletal muscle differentiation as a model, our work will provide molecular mechanisms defining how signaling pathways modify a specific chromatin remodeling enzyme to mediate embryonic and adult skeletal muscle differentiation and maintenance. The work will have significant impact on our overall understanding of muscle development in the embryo and muscle regeneration in the adult. This work will also increase our understanding of changes that occur in muscle diseases where increased muscle growth (hypertrophy) or reduced muscle development (hypotrophy) are exhibited and on the formation of rhabdomyosarcomas, which are tumors of myogenic derivation.
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