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Adaptive changes in contractile proteins are thought to underlie important alterations in the performance of cardiac and skeletal muscles. Myosin, a major component of the contractile apparatus, is known to participate in such changes. This protein is comprised of two heavy chains and 4 to 6 light chains. Distinct myosin heavy chain (MHC) isoforms with different ATPase activities are found in cardiac and skeletal muscles. The relative proportions of the isoforms may be physiologically significant since the speed of muscle contraction is related to myosin ATPase activity.
Studies in this laboratory are directed toward understanding the molecular basis for MHC gene regulation. At least seven MHC genes are known to be expressed in striated muscle. Expression of these MHC genes has been shown to be subject to developmental and innervational controls. In addition, all of the MHC genes appear to be regulated by thyroid hormone in a highly complex manner.
The actions of thyroid hormone are thought to be mediated by binding of the hormone to nuclear receptors, which is associated with alterations in expression of a small number of genes. The details of this process are poorly understood, but studies of gene responses to steroid hormones and polypeptide hormones have suggested that DNA sequences of the 5' flanking region are important. These elements are thought to be recognized by DNA-binding proteins, including the thyroid hormone receptor.
We are investigating the DNA sequences and DNA binding proteins required for regulation of MHC gene expression. A variety of methodologies are employed, including cardiac cell culture and recombinant DNA techniques. Synthetic myosin genes containing 5' flanking sequences are introduced into cultured heart cells where they can be controlled by thyroid hormone. This permits the identification of DNA sequences required for thyroid hormone control. Once the sequences are defined, binding studies with nuclear extracts are carried out to find specific DNA-binding proteins. Ultimately, these proteins can be cloned and sequenced. Taken together, it is hoped this approach will provide a relatively complete picture of MHC gene control.