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)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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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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Conerly, Melissa L; Yao, Zizhen; Zhong, Jun Wen et al. (2016) Distinct Activities of Myf5 and MyoD Indicate Separate Roles in Skeletal Muscle Lineage Specification and Differentiation. Dev Cell 36:375-85
Fong, Abraham P; Yao, Zizhen; Zhong, Jun Wen et al. (2015) Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage. Cell Rep 10:1937-46
Yang, Z J P; Broz, D Kenzelmann; Noderer, W L et al. (2015) p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress. Cell Death Differ 22:560-73
Yao, Zizhen; Macquarrie, Kyle L; Fong, Abraham P et al. (2014) Discriminative motif analysis of high-throughput dataset. Bioinformatics 30:775-83
Yao, Zizhen; Farr 3rd, Gist H; Tapscott, Stephen J et al. (2013) Pbx and Prdm1a transcription factors differentially regulate subsets of the fast skeletal muscle program in zebrafish. Biol Open 2:546-55
Diede, Scott J; Yao, Zizhen; Keyes, C Chip et al. (2013) Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer. Epigenetics 8:1254-60
Dey, Joyoti; Dubuc, Adrian M; Pedro, Kyle D et al. (2013) MyoD is a tumor suppressor gene in medulloblastoma. Cancer Res 73:6828-37
Fong, Abraham P; Tapscott, Stephen J (2013) Skeletal muscle programming and re-programming. Curr Opin Genet Dev 23:568-73
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
Yao, Zizhen; Fong, Abraham P; Cao, Yi et al. (2013) Comparison of endogenous and overexpressed MyoD shows enhanced binding of physiologically bound sites. Skelet Muscle 3:8

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