Regulation of gene expression by chromatin remodeling enzymes

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PROJECT SUMMARY 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. The mammalian SWI/SNF (mSWI/SNF) enzyme family members 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 can act as tumor suppressors or tumor promoters. Additionally, SWI/SNF enzymes 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 in proliferating and differentiating myoblasts. We will employ methods to manipulate the expression of specific kinases, phosphatases and remodeling enzyme subunits and will manipulate function through use of inhibitors and mutagenensis. We will analyaze the effects of such approaches on gene expression, chromatin binding and remodeling, transcription factor function, local higher-order gene structure, and overall genome organization. The work will provide new paradigms for understanding how signaling molecules converge on chromatin to regulate tissue differentiation and development.