The Death of Transcriptional Chauvinismin the Control and Regulationof Cardiac Contractility

摘要

In the last 25 years we have witnessed the triumph of the genome. There are now well over 200complete genome sequences. The application of modern solid state technologies to genomic se-quencing promises affordable personalized sequences for the individual in the very near future.With this explosion in DNA sequence data, the focus in the immediate past has been on the primaryDNA sequence, the cis-trans interactions that underlie controlled transcription, cataloging the tran-scriptome, and applying rudimentary systems analysis to those data sets in an attempt to assignmolecular signatures to normal and abnormal physiological states. However, it is becoming clearthat the post-transcriptional processes, which operate at the levels of RNA stability and selectionfor translational initiation, as well as the post-translational processes of protein stability, traffick-ing, and secondary modifications, such as phosphorylation, all play key roles in the homeostasisof the contractile apparatus and its overall function. Defining the interplay of these processes, inconcert with the signaling pathways that allow transcription, translation, and post-translationalprocesses to be quickly modified in response to events outside of the cardiomyocyte are leadingto an understanding of the spatial and temporal requirements for each of these processes in con-trolling cardiac output. In order to confirm the importance of post-translational modification incontrolling cardiac contractility in vivo, we examined the role that post-translational modifica-tion of an important component of the cardiac contractile apparatus, myosin binding protein C(MyBP-C), plays in the normal and diseased heart by creating transgenic mice in which the effectsof chronic cardiac MyBP-C phosphorylation and dephosphorylation could be determined.