TISSUE-SPECIFIC CONTROL OF MUSCLE GENE EXPRESSION

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Skeletal muscle differentiation is accompanied by the coordinate induction of sarcomeric proteins. The appearance of these proteins is preceded by a rise in the abundance of the corresponding mRNAs reflecting an increase in transcriptional activity. This transcriptional increase, in turn, is dependent upon the presence of the correct cis- and trans- acting elements. We have recently identified a nuclear factor in skeletal muscle which binds specifically and with high affinity to an upstream sequence element located 5' to the genes encoding the sarcomeric proteins, a-actin and myosin light chain 2. This finding lends support to the hypothesis that the sarcomeric proteins are coordinately induced through the action of a limited number of trans-acting factors. In the present application, we propose to extend these observations by (i) Delineating the role of the upstream muscle specific, sequence element in the regulation muscle gene expression (ii) Purifying and characterizing the skeletal muscle nuclear factor(s) that bind to this sequence (iii) Developing an in vitro transcription system with which to rigorously assess the regulatory function of muscle specific factors. Our goal, the purification of trans-acting factors and the elucidation of the role of DNA binding sequences in tissue-specific gene regulation, is the first step in understanding the developmental cascade which eventually results in myoblast differentiation.