During the complex process of heart formation, a subset of cells is directed to form the cardiac conduction system. By understanding how this process takes place, we hope to uncover how normal human cardiac rhythm is established and pathological arrhythmias are generated. Our lab focuses on the following three broad biological questions:
How are cell fate decisions made?
A choice is made during heart development whether a cardiac progenitor cell will continue down the myocardial lineage or become a conduction cell. Although many aspects of this process have been investigated, additional transcriptional pathways remain to be identified.
In order to address this question, we have created a transgenic mouse that marks AV nodal cells to identify transcription factors enriched in the cardiac conduction system. Through a variety of validation methods, we have generated a list of transcription factors requiring further detailed characterization. We plan to study knockout and transgenic animals to gain a better understanding of how these transcription factors impact conduction cell fate.
What is the cis-regulatory logic governing the choice and maintenance of a specific developmental fate?
Once a cardiac progenitor cell has made the decision to become a conduction cell, it must faithfully execute a transcriptional program to adopt and maintain this fate. Our prior studies have attempted to address this question by deciphering the cis-regulatory logic underlying Cx30.2 expression in the mouse AV node.
We plan to continue detailed analysis of the Cx30.2 enhancer and also characterize the cis-regulatory sequences of additional enhancers to gain further insight into the logic governing execution of these transcriptional programs. Furthermore, we plan to develop novel techniques to interrogate the cis-regulatory architecture of the AV node at the whole-genomic level.
How do these mechanisms impact normal and pathological cardiac rhythms?
Execution of specific gene expression programs directed by specific sets of transcription factors orchestrates cardiac conduction system formation and function. However, how these pathways contribute to normal and pathological cardiac rhythm remains to be clarified.
We will continue to use mouse as a model organism to determine which transcriptional pathways impact cardiac conduction system formation and function. Additionally, we plan to test whether individual components of these pathways affect normal cardiac electrical activation or contribute to the genesis of cardiac arrhythmias.