Programmed terminal differentiation of cardiac myocytes is vital for reorganizing the heart's structure and function to meet basic physiologic demands. Many of these differentiation mechanisms are redeployed after ischemic injury or in the context of heart disease. While terminal differentiation is indispensable for basic cardiac function this fate change is associated with the nearly complete cessation of myocyte proliferation, which underlies one of the major barriers in the treatment of ischemic heart disease- the lack of effective therapeutic strategies to remuscularize the fibrotic heart. Many differentiation mechanisms are redeployed after injury, but it's unclear whether the response is adaptive or pathologic, thus understanding how the flow of genetic information establishes and maintains myocyte differentiation improves our current knowledge of basic cardiac physiology and provides insights into cardiac regeneration and disease. Much of our knowledge about terminal differentiation has come from investigating gene regulatory mechanisms at the level of DNA and epigenetics with little attention paid to post-transcriptional control of the cardiac transcriptome. Here we are hijacking the function of a highly conserved RNA-binding protein muscle blind like-1 (MBNL1) to understand how transcriptional reprogramming of myocyte terminal differentiation impacts post natal development and post-infarct regenerative and pathologic remodeling. Specifically, this application will use an array of gain and loss of function mouse models that permit cardiac myocyte specific temporal dosing of MBNL1 to reprogram the heart's transcriptome to achieve the following aims: (1) determine the role of MBNL1-dependent transcriptome reprogramming in establishing and maintaining cardiac myocyte differentiation, (2) define the role of MBNL1-dependent transcriptome reprogramming in post-infarct regenerative and pathologic myocyte remodeling, and (3) determine context dependent regulatory mechanisms underlying MBNL1-dependent transcriptome reprogramming. Data from these aims will identify potential mechanisms by which transcriptional reprogramming can be used to control either endogenous or stem-cell derived myocyte fate as a novel therapeutic strategy for cardiac remodeling and regeneration.
This project addresses how post-transcriptional control mechanisms regulate myocyte differentiation. The switch from a proliferative to differentiated cell fate is important for both post- natal heart development and pathologic versus regenerative cardiac remodeling. Transcriptome regulation by RNA binding proteins has not been studied in this context, but understanding these mechanisms would allow us to determine whether transcriptional reprogramming of myocytes could benefit cardiac repair by unmasking latent regenerative pathways that may still be present but silenced in the adult heart, thereby serving as a possible strategy for dealing with the loss of cardiac muscle and ensuing cardiac dysfunction associated with ischemic heart disease like myocardial infarction.
