Each cell type in our body has its own identity. This identity allows a heart cell to contract repetitively, and a brain cell to conduct nerve impulses. Each cell type gains its identity by turning on or off thousands of genes that together give the cell its identity. Understanding how these sets of genes are regulated together as a cell gains its identity is important to be able to generate new cells in disease. For example, after a heart attack, heart muscle dies, leaving scar tissue and a poorly functioning heart. It would be very useful to be able to make new heart muscle by introducing the right set of instructions into other cells in the heart, and turn them into new heart muscle cells. One way that many genes are turned on or off together is by a cellular mechanism called epigenetic regulation. This global regulation coordinates thousands of genes. We plan to understand the epigenetic regulatory mechanisms that give a human heart muscle cell its identity. Understanding their epigenetic blueprint of cardiac muscle cells will help develop strategies for cardiac regeneration, and for a deeper understanding of how cells in our body acquire their individual identities and function.
This research will benefit the state of California and its citizens by helping develop new approaches to cardiac regeneration that will be more efficient than current approaches, and amenable to drug-based approaches. In addition, the knowledge acquired in these studies will be important not only for heart disease, but for any other disease where reprogramming to regenerate new cells is desirable. The mechanisms revealed by this research will also lead to new understanding of the basis for congenital heart defects, which affect several thousand Californian children every year, and for which we understand very little.
The goal of this proposal is to define an epigenetic blueprint of human cardiomyocyte differentiation. Epigenetic modifications are dynamic changes to DNA that regulate gene expression. The applicant hypothesizes that a detailed understanding of these changes during cardiomyocyte differentiation is critical to understanding the adoption of this cell fate. In addition, this knowledge is expected to inform strategies for cardiomyocyte regeneration as well as to give insights to the defects in congenital heart disease (CHD). For Aim 1, epigenetic chromatin modifications will be mapped at multiple stages of human cardiomyocyte differentiation from both embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC). For Aim 2, epigenetic maps and gene expression profiles will be defined for cardiomyocytes of the two major lineages. Finally, for Aim 3, human cardiomyocytes and cardiomyocyte precursors carrying a mutation found in CHD will be epigenetically mapped.
Significance and Innovation
- These studies will provide for the first time a detailed and dynamic epigenetic profile of human cardiomyocyte differentiation from a pluripotent stem cell. This information will be a significant resource for the field.
- The results of this work should provide valuable insight into the mechanism of cardiomyocyte differentiation, which is directly applicable to cardiac regeneration as well as congenital heart disease.
- Innovative aspects include identification of distal enhancer elements that are key for cardiomyocyte differentiation, as well as the study of cardiomyocytes derived from congenital heart disease iPSCs.
Feasibility and Experimental Design
- The extensive preliminary data, established expertise, and the availability of reagents convinced reviewers that the investigator would be successful in carrying out the proposed studies.
- The reviewers felt that the studies were well designed, although more descriptive than hypothesis-driven.
Principal Investigator (PI) and Research Team
- The PI is an outstanding established investigator in the field of cardiac differentiation, with an excellent track record in studying epigenetic regulation of cardiomyogenesis.
- The collaborators provide additional needed expertise.
Responsiveness to the RFA
- The application is responsive to the RFA. It proposes to investigate basic aspects of human stem cell biology as well as the molecular basis of a human disease.
- James Ellis