Our preliminary studies suggest that Myf5 functions to modify the epigenome in preparation for subsequent transcriptional activation by MyoD, Myogenin and MRF4. Confirming this model will establish a new paradigm for hierarchical families of transcription factors and demonstrate the separation of epigenetic and transcriptional function within members of the same closely related family.
Aim 1 will test the hypothesis that the major biological role of Myf5 is to establish active chromatin domains around genes that will be transcribed later in the differentiation program.
This aim will extend the preliminary studies and will determine whether Myf5 has predominantly chromatin remodeling activities genome-wide that prepare regions of the genome for transcriptional activation of muscle genes by MyoD and Myogenin.
Aim 2 will test the hypothesis that the epigenetic activity of Myf5 prepares genes for subsequent transcriptional activation by Myogenin or MRF4.
This aim will determine whether the epigenetic activity of Myf5 facilitates the subsequent DNA binding and transcriptional activity of Myogenin or MRF4 on the expression of the skeletal muscle program.
Aim 3 will test the hypothesis that Myf5 has an epigenetic role in mouse muscle development but requires the transcriptional activity of MyoD, Myogenin, or MRF4 for myogenic differentiation of primary mouse myoblasts. Genetic studies have shown that MyoD and Myf5 have largely redundant roles in muscle development and differentiation.
This aim will determine whether Myf5 has a distinct epigenetic function in primary mouse muscle cells. Together these studies will provide a new framework for studying the molecular basis of lineage commitment and cell specification in normal development and in cancers.

Public Health Relevance

The proposed research will identify the fundamental molecular mechanisms that specify a cell to become a specific cell type, e.g., a muscle cell. The health relevance of this research is that the failure of these mechanisms might comprise the initial steps in cancer formation or other developmental diseases. Therefore, identifying the molecular mechanisms of cell specification will provide new approaches to understanding human disease and for developing future therapies.

National Institute of Health (NIH)
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Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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Fred Hutchinson Cancer Research Center
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Yao, Zizhen; Macquarrie, Kyle L; Fong, Abraham P et al. (2014) Discriminative motif analysis of high-throughput dataset. Bioinformatics 30:775-83
MacQuarrie, Kyle L; Yao, Zizhen; Fong, Abraham P et al. (2013) Comparison of genome-wide binding of MyoD in normal human myogenic cells and rhabdomyosarcomas identifies regional and local suppression of promyogenic transcription factors. Mol Cell Biol 33:773-84
Sebastian, Soji; Faralli, Herve; Yao, Zizhen et al. (2013) Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation. Genes Dev 27:1247-59
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Mahoney, Sarah E; Yao, Zizhen; Keyes, C Chip et al. (2012) Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas. Epigenetics 7:400-8
Conerly, Melissa L; MacQuarrie, Kyle L; Fong, Abraham P et al. (2011) Polycomb-mediated repression during terminal differentiation: what don't you want to be when you grow up? Genes Dev 25:997-1003
Gianakopoulos, Peter J; Mehta, Virja; Voronova, Anastassia et al. (2011) MyoD directly up-regulates premyogenic mesoderm factors during induction of skeletal myogenesis in stem cells. J Biol Chem 286:2517-25
MacQuarrie, Kyle L; Fong, Abraham P; Morse, Randall H et al. (2011) Genome-wide transcription factor binding: beyond direct target regulation. Trends Genet 27:141-8

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