Cell fate decisions during cardiac lineage commitment are highly orchestrated processes requiring precisely co-activated or repressed gene expression at the genome level. However, how extrinsic and intrinsic signals coordinate to dictate cardiac cell fate decision remains to be determined. In recent years, pluripotent stem cells (PSCs) have gained popularity as ideal cell candidates for mammalian developmental studies and regenerative medicine. Thus, direct derivation of cardiac cells from pluripotent stem cells offers a unique platform to dissect molecular basis of cardiac cell fate decision during development.
Previous studies indicated critical roles of epigenetic regulation, which grants chromatin architecture with instructive and programmatic roles in delicate gene expression network, in cell fate decision. However, the precise functions of epigenetic regulation in cardiac lineage commitment from pluripotent stem cells remains unclear. The long-term goal of our lab is to systematically define how epigenetic regulation dictates cell fate transitions in cardiac lineage commitment from pluripotent stem cells (PSCs), which will build the foundation allowing us to manipulate cell fate in development and diseases by regulating chromatin organization. We are investigating the following aspects:
- To determine the role of epigenetic regulation in cardiac lineage commitment.
Growing studies suggest a critical role of chromatin organization in normal cardiogenesis and congenital heart defects (CHD). However, the precise functions of chromatin regulators in human cardiac development have been elusive due to the limited access to human embryonic specimens. Human PSCs-based cardiac differentiation model provides us a unique platform to study the molecular events in human cardiac development and CHD. Therefore, we will take the advantage of PSC-based cardiac differentiation model to study the molecular mechanisms of epigenetic regulation in cell fate transitions during cardiac lineage commitment, which will provide the insights in the prevention and invention of CHD.
- To explore the role of dysregulated epigenetic factors in cardiac diseases.
Cardiac hypertrophy and failure is a chronic process and is characterized by abnormal chromatin organization and transcriptional reprogramming of gene expression. Previous studies indicated that the dysregulation of epigenetic factors, especially those which have critical roles in normal heart development, led to abnormal dedifferentiation of cardiomyocytes (CMs) under stress conditions, and subsequent hypertrophic cardiomyopathy (HCM). Thus, understanding the roles of dysregulated epigenetic factors in HCM will provide mechanistic insights into abnormal cardiac cell fate conversion under pathological conditions, and open new avenues for disease prevention and intervention.
- Systematically characterize the roles of epigenetic regulation in PSC-cardiac lineage commitment.
Dynamic chromatin structure acts as a critical hub integrating external signals and internal cellular responses to precisely control gene expression programs, and thereby assures the precise execution of normal development. However, how epigenetic factors coordinate with each other to regulate the transitions of chromatin structure in cardiac lineage commitment remains unclear. We are using the existing cardiac differentiation platforms to perform open-ended genetic screens to systematically identify epigenetic factors important for cardiac lineage commitment. These studies will give us a comprehensive view of how epigenetic regulators coordinate with each other to establish specific chromatin structure regulating distinct gene expression programs in cell fate decision during cardiac lineage commitment.