Sumoylation is an important post-translational modification that alters the 
activity of many transcription factors. However, the mechanisms that link 
sumoylation to alterations in chromatin structure, which culminate in tissue 
specific gene expression, are not fully understood. In this study, we 
demonstrate that SUMO modification of the transcription factor Sharp-1 is 
required for its full transcriptional repression activity and function as an 
inhibitor of skeletal muscle differentiation. Sharp-1 is modified by sumoylation 
at two conserved lysine residues 240 and 255. Mutation of these SUMO acceptor 
sites in Sharp-1 does not impact its subcellular localization but attenuates its 
ability to act as a transcriptional repressor and inhibit myogenic 
differentiation. Consistently, co-expression of the SUMO protease SENP1 with 
wild type Sharp-1 abrogates Sharp-1-dependent inhibition of myogenesis. 
Interestingly, sumoylation acts as a signal for recruitment of the co-repressor 
G9a. Thus, enrichment of G9a, and histone H3 lysine 9 dimethylation (H3K9me2), a 
signature of G9a activity, is dramatically reduced at muscle promoters in cells 
expressing sumoylation-defective Sharp-1. Our findings demonstrate how 
sumoylation of Sharp-1 exerts an impact on chromatin structure and 
transcriptional repression of muscle gene expression through recruitment of G9a.