The long term goal of these studies is to define the transcriptional programs controlling the determination and differentiation of skeletal, cardiac, and smooth muscle. Efforts to initiate or inhibit muscle cell growth and differentiation following injury, disease, or as a result of congenital abnormalities require a greater understanding of basic genetic control within these lineages. The identification of the transcription factors regulating muscle specific gene expression and defining how these regulators function is critical to understanding the mechanisms controlling myogenesis in vivo. The hypothesis for these studies is that transcriptional regulation of myogenesis is controlled by multiple sets of transcription factors which function combinatorially to drive gene expression in a unique temporospatial pattern within each distinct muscle lineage. For example, transcription factors of the myocyte enhancer factor 2 (MEF2) and MyoD families are essential cofactors for one another and function combinatorially to induce myogenesis in skeletal muscle. Evidence suggests that MEF2 proteins also function combinatorially to induce differentiation of cardiac and smooth muscle. However, to date no """"""""MyoD equivalents"""""""" serving as coregulators for MEF2 have been isolated from other muscle lineages. The studies proposed in this application are designed to identify transcriptional regulators in cardiac and smooth muscle that are comparable to MyoD in that they induce myogenesis and gene expression through combinatorial interactions with MEF2 factors.
The specific aims of this proposal are: 1) To define the transcriptional regulation of HRC, a gene which is expressed in all three muscle lineages in mammals during development and in adults. Preliminary data suggests that MEF2 factors collaborate with previously unidentified DNA binding proteins to direct expression of HRC in cardiac and smooth muscle lineages. 2) To identify MEF2 coregulators comparable to MyoD in smooth and cardiac muscle.
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