Proliferation into differentiation is a hallmark of biological systems that undergo differentiation. Skeletal muscle differentiation has long been a model for studying other differentiation process. The process is initiated by the formation of precursor myoblast cells. Defects in this program is linked to degenerative diseases, muscle loss and muscle tumors. Proliferation into differentiation of myoblasts involves activation of genes that specify muscle. Thus, studying the regulation of differentiation responsible gene expression in this model system will provide insight into other cell-specific differentiation program and its importance in disease. The transcriptional regulator MyoD is essential for myoblasts formation and differentiation. Although MyoD is expressed in myoblasts, it does not activate genes in switching myoblasts to differentiate without the stimulus of differentiation. MyoD function in inducing differentiation is deregulated in rhabdomyosarcoma (RMS). The long-term goal of this application is to identify mechanism that regulates MyoD in the balance between proliferation and differentiation. This proposal will address the role of MyoD in chromatin modification in the regulation of differentiation responsible gene expression. By interacting with histone deacetylase (HDAC), MyoD inhibits muscle gene expression and differentiation. Our preliminary data indicate that histone methyltransferase Suv39h1, which is involved in gene silencing, inhibits MyoD activity. Moreover, forced activation of promyogenic pSSMAPK overcomes this inhibitory effect. In this proposal, we propose the hypotheses that (i) MyoD establishes an epigenetic gene silencing mechanism in myoblast cells to prevent to differentiation, and (ii) Differentiation-dependent stimulus modulates chromatin proceeding myoblast cells to differentiate. We will test these hypotheses by pursuing the following specific aims: (1) To define whether MyoD establishes an epigenetic gene silencing mechanism in myoblast cells to prevent differentiation. (2) To determine whether differentiation-dependent stimulus modulats chromatin proceeding myoblast cells to differentiate. (3) To identify whether the deficiency in differentiation-dependent stimulus sustains muscle genes in silenced chromatin preventing rhabdomyosarcoma (RMS) cells differentiation. It is our expectation that completion of these AIMS will lead to novel therapies for muscle-related diseases.
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