To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote 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 differentiation. We have made extensive use of cell culture models to identify and characterize chromatin remodeling enzyme function during skeletal muscle differentiation. Via modification of existing methodologies, we are now also capable of examining changes in chromatin structure and regulatory protein interactions that lead to gene activation during embryonic myogenesis and during the activation and maintenance of gene expression in adult tissue. Recent advances allow us to examine the regulation of myogenic gene expression specifically in the somites, at the start of myogenesis in the embryo, which further extends our abilities to understand the molecular control of myogenesis in the context of embryonic development. This renewal application will focus on SWI/SNF chromatin remodeling enzyme function at several levels. We will investigate how SWI/SNF enzymes cooperate with myogenic transcription factors and histone modifying enzymes to promote temporal control of myogenic gene expression (AIm 1). We will investigate how signal transduction pathways required for myogenesis regulate chromatin remodeling enzyme function (Aim 2). Finally, we will investigate SWI/SNF chromatin remodeling enzyme function in the differentiation dependent rearrangement of myogenic gene positioning in the nucleus and how this process contributes to the temporal control of myogenic gene expression (Aim 3).
Our proposed studies addressing the regulation of tissue-specific gene expression during embryonic and adult skeletal muscle differentiation and maintenance at a molecular level 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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