The human body is composed of thousands of cell types, which all came originally from embryonic stem cells. Although all these cell types have the same genetic blueprint, different genes are active in different cells to give each its distinctiveness. The process by which the genes remember whether they are in liver, brain, or skin cells is called “epigenetics.” A central problem in regenerative medicine is to understand the epigenetic program so that human embryonic stem cells can be efficiently turned into the cell types required for each specific patient.
The goal of the proposed research is to better understand the epigenetic program in human embryonic stem cells and adult cells. We want to tap into the natural mechanisms by which the body normally “remembers” what kinds of cells reside in each tissue and apply them to regenerative therapies. Specifically, the research will study the roles of a newly discovered type of genes, termed “long noncoding RNAs" or lncRNAs.
A better understanding of lncRNAs can improve regenerative medicine in several ways. First, specific lncRNAs can be used as markers to track and predict when cells are acquiring or forgetting specific cell fates. Second, manipulation of lncRNAs and their protein partners may allow cells to change or commit to specific cell fates. This research will specifically focus on how stem cells commit to specific cell fates, by locking genes into the "ON" state.
The proposed research can benefit the state of the California in three ways. First, the research will generate important knowledge on new ways to manipulate cell fate potentials of stem cells and mature adult cells. This information could speed the development of regenerative medicine in California, benefiting patients with currently untreatable diseases.
Secondly, this research will develop new molecules and engineered stem cell lines that can be used to manipulate cell fates. These technological advances may have commercial value for the biotechnology industry.
Finally, the proposed research will train young scientists to become skilled in human stem cell research. Graduate Ph.D. students and postdoctoral fellows in this California-based institution will gain the hands-on experience and expertise of manipulating human stem cells and of reprogramming adult cells. The training and experience of these young scientists will prepare them to develop new regenerative therapies, launch new companies based on stem cells, or teach future students about regenerative medicine.
The goal of this proposal is to explore the role of long noncoding RNA molecules (lncRNAs) in the biology of pluripotent stem cells. LncRNAs comprise a newly recognized class of epigenetic regulators that are thought to recruit chromatin remodeling factors to specific sites in the genome, thereby affecting expression of nearby genes by turning them ìonî or ìoffî. To determine the molecular mechanisms by which lncRNAs contribute to stem cell fate, the applicant has proposed two aims. First, a screening approach will be used to identify and characterize lncRNAs associated with a specific type of binding site in human embryonic stem cells (hESCs). Next, the mechanisms by which lncRNAs lock chromatin into active or inactive states will be explored by testing a novel hypothesis on the means by which lncRNAs interact with their molecular partners.
Significance and Innovation
- The proposal is highly innovative and addresses an underexplored area of stem cell biology.
- If successful, the proposed research could provide novel insights on lncRNA function and gene regulation in hESCs, with a broader impact on the development of improved strategies for controlling cell fate.
Feasibility and Experimental Design
- The proposed studies are logical and achievable within the given timeframe. Potential pitfalls and alternative approaches have been provided.
- Project feasibility is supported by robust preliminary data, most of which was generated using mouse cells. Reviewer enthusiasm was slightly tempered by the lack of significant data from hESC.
Principal Investigator (PI) and Research Team
- The PI is exceptionally well qualified, having made seminal discoveries in relevant areas of the field.
- Excellent collaborators have been recruited to provide expertise in computational biology and embryonic stem cell science. The research environment is outstanding.
Responsiveness to the RFA
- The proposed research is responsive, as it utilizes human stem cells and is focused on molecular mechanisms.