Long noncoding RNAs for pluripotency and cell fate commitment
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.
While all cells in the body share the same genetic material in DNA, different cell types can turn different genes on or off by controlling the access to DNA. DNA is wound up like a spool with proteins in a complex called chromatin. Stem cells can choose and commit to different cell fates by carefully rearranging the organization of chromatin. Our research has shown that a new class of genes called long noncoding RNAs appear to have an important role in telling which genes stay on. This occurs by the RNAs talking to proteins that keep chromatin in an active configuration. We have also developed new methods to measure the location of open chromatin sites much more rapidly and sensitively than previously possible.
The main goal of this project is to understand how stem cells choose what kind of cells to be, particular through newly recognized molecules called long noncoding RNAs. We found that specific long RNAs are involved in keeping embryonic stem cells in a stem cell state, while other ones help stem cells turn into particular tissues, like brain or skin. We found special chemical tags on the RNAs, called RNA modifications, are important for the RNAs to function properly. Thus controlling how RNA modifications are written or erased may be a new way to manipulate stem cells for research and clinical applications.
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- Cell Stem Cell (2014) Long Noncoding RNAs in Cell-Fate Programming and Reprogramming. (PubMed: 24905165)
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- Cell Stem Cell (2014) m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. (PubMed: 25456834)
- Nat Methods (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. (PubMed: 24097267)