Our long-term goal is to understand the synergism between MyoD and chromatin-modifying factors in the control of skeletal myogenesis. Work from our laboratory has revealed that MyoD's activities in undifferentiated myoblasts are controlled through its association with a class 1 histone deacetylase (HDAC), or by a histone acetyltransferase (HAT) as differentiation occurs. Our new studies indicate that the interaction between MyoD and HDAC1 on chromatin may now define a new mechanism by which musclespecific genes are kept in a repressed state until myoblasts are induced to differentiate. Our purpose is to explore this new function of MyoD, and in addition, pursue studies that identify the HDACs and HATs that specifically interact with MyoD at the promoters of muscle-specific genes in undifferentiated and differentiated muscle cells, respectively. Experiments are also proposed to determine whether these two enzymes are functioning with MyoD through a circuitry that include other chromatin remodeling factors (e.g., methylases, HP1, and SWl/SNF).
In Aim 1, we plan to investigate whether MyoD is serving a general role in repressing muscle-specific genes prior to muscle differentiation, and with the help of chromatin modifying factors. Experiments to determine whether MyoD is recruiting an HDAC to promoters for affecting chromatin structure, specifically the 'markings' of histones, are also proposed.
In Aim 2, we plan to explore whether MyoD is occupying the promoters of muscle genes along with P/CAF and/or p300/CBP once differentiation occurs, and if so, perform studies to determine whether their recruitment depends on MyoD. We also plan to investigate whether MyoD cross talks with HATs to establish a pattern of histone acetylation within the promoters of muscle-specific genes, and if so, conduct kinectic studies to determine whether this correlates to their expression. Finally, we plan to determine whether there is a functional link between phosphorylation and acetylation in regulating MyoD's ability to activate MyoD-responsive genes upon differentiation.
| Zhang, Keman; Sha, Jingfeng; Harter, Marian L (2010) Activation of Cdc6 by MyoD is associated with the expansion of quiescent myogenic satellite cells. J Cell Biol 188:39-48 |
| Zhang, Keman; Sha, Jingfeng; Harter, Marian L (2010) MyoD, a new function: ensuring ""DNA licensing"". Cell Cycle 9:1871-2 |
