Transcriptional Regulation of Human Embryonic Stem Cells
Transcriptional Regulation of Human Embryonic Stem Cells
Stem Cell Use:
Embryonic Stem Cell
Embryonic Stem (ES) cells can be grown indefinitely in the lab and can be turned into any cell type of the human body. Because of these properties, it may one day be possible to use ES cells to generate cell types in the lab that can then be transplanted into patients that need them. This approach may provide new treatments for devastating and presently incurable conditions such as type I diabetes, Parkinson’s disease, muscular dystrophies, spinal cord injuries, and many others. However, before human ES cells can safely be used in the clinic, it will be essential to understand how they function. For example, if rapid cell division is not kept in check in ES cells, they can give rise to tumors upon transplantation. Our proposal is directly aimed at understanding the genetic regulation of human ES cells. We developed a very innovative approach to understand how gene activity is regulated in human ES cells. Our very significant progress so far it can be summarized as follows:- we identified the genes that are preferentially activated in ES cells;- we discovered several DNA sequences that act as genetic switches to turn ES cell genes on or off;- we identified an operator protein that activates one of these switches;- we discovered that this protein is essential to maintain rapid cell division of mouse ES cells.We now propose to investigate the function of this protein in human ES cells. We further propose to identify other operator proteins that activate genetic switches revealed by our work. Our ultimate goal is to identify all the operator proteins, the corresponding genetic switches, and their combined mode of action in human ES cells. We expect that this research will make the following significant contributions:1. Our research may lead to the development of diagnostic tests that detect the activity of the operator proteins and genetic switches that we have identified. These diagnostic tests may be important tools for quality control of human ES cells;2. The operator proteins identified are expected to be critical regulators of rapid cell division of human ES cells. Understanding what those operator proteins are may lead to the development of new drugs to prevent the formation of tumors upon transplantation of ES cells;3. The current methods to obtain a particular cell type from ES cells still result in a mixture of different cell types. If we understand how genes are activated in ES cells, we may be able to turn on the precise set of genes that leads to the formation of a particular cell type of interest, and thus obtain pure populations of cells needed by patients;4. If we understand what are the essential operator proteins that regulate gene activity in ES cells, we may be able to formulate a cocktail of these proteins that is capable of resetting the genetic program of a patient’s own cells back to that of ES cells. This way the transplanted cells will be immune-matched to the patient, and therefore will not be rejected.
Statement of Benefit to California:
Human embryonic stem cells hold the potential to revolutionize medicine and health care. Research on human embryonic stem cells may provide new treatments for devastating and presently incurable conditions such as type I diabetes, Parkinson’s disease, muscular dystrophies, spinal cord injuries, and more than 70 other diseases. We anticipate that our research will be a significant step towards making the promise of human embryonic stem cells a reality. Our proposal aims to identify genes that regulate the properties of human embryonic stem cells. This research will pave the way for the development of safe clinical applications of human embryonic stem cells. If we understand the genetic mechanisms that regulate human embryonic stem cells, we will be able to manipulate those mechanisms so as to obtain cell types of therapeutic value, while avoiding unintended side-effects. The development of human embryonic stem cell-based therapies will significantly increase the options available in the California health care system. These new therapies are expected to reduce the long-term health care costs to California by providing cures to diseases that are currently chronic and require expensive periodic treatment. Our research is also expected to stimulate the development of biotechnology industry focused on clinical applications of human embryonic stem cells. Such development will be of great benefit to California by attracting high-skill jobs and tax revenues, and by making the State a leader in a field that is poised to be the economic engine of the future. The State of California will also stand to benefit from the intellectual property generated by this research.
Year 1A central goal of our CIRM SEED proposal was to use innovative unbiased approaches to discover novel proteins that turn genes on or off in pluripotent stem cells. An understanding of what are these proteins that act as genetic switches and how they function is of significant importance to efforts to use pluripotent stem cells to model disease states in the lab or to provide a source of cells of therapeutic interest for transplantation. We have been successful in our efforts, in that we identified a novel protein that appears to play an unexpected role in the regulation of gene activity in pluripotent stem cells. In addition, we have identified another protein that is critical to maintain the DNA of pluripotent stem cells is a state accessible to other proteins. Our research is therefore providing an integrated picture of what are the genetic switches that turn genes on or off in pluripotent stem cells, what genes do they regulate, and how is their access to DNA regulated. Some of our results have recently been published, while other research is ongoing. In parallel, we have been very successful at transferring expertise to the biotechnology sector in California. In particular, two highly qualified lab members accepted senior scientist positions at top biotechnology firms in California (iPierian and Genentech).
Year 2A central goal of our CIRM SEED proposal was to use innovative approaches to discover genes that control human embryonic stem cells, with the idea that this knowledge may lead to improved methods for growth and/or differentiation of human pluripotent stem cells in a clinical setting. In the past year we have continued to make significant progress on these efforts. We have found a factor that acts to turn other genes on or off and is active in embryonic stem cells. We have put a considerable amount of effort into optimizing methods to identify exactly what genes this factor controls. Our results show that this factor directly regulates pluripotency-associated genes. This is remarkable, since this factor had not to date been implicated in the regulation of pluripotency. These results put us in a position to characterize the function of this factor in embryonic stem cells in greater detail. In addition, we are applying knowledge gained from our studies to develop methods to enhance the ease with which human pluripotent stem cells are propagated. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, are notoriously more difficult to grow than their mouse counterparts, and this has significantly hampered the ability to use existing human pluripotent stem cells to model disease. We have developed conditions that facilitate the propagation of human pluripotent stem cells in a state that resembles mouse ES cells, where they are easier to propagate and grow more rapidly. These findings, while preliminary, suggest that we have the opportunity to explore a transition of human pluripotent stem cells to a state that is easier to culture and manipulate genetically. Thus, the CIRM SEED award has allowed us to discover a novel regulator of pluripotency genes, and to develop conditions that may lead to improved culture and manipulation of human pluripotent stem cells.
- Nat Rev Mol Cell Biol (2011) Open chromatin in pluripotency and reprogramming. (PubMed: 21179060)
- Curr Opin Genet Dev (2010) Parallel gateways to pluripotency: open chromatin in stem cells and development. (PubMed: 20598875)
- Cell (2009) iPS cells: insights into basic biology. (PubMed: 19703387)
- Nature (2009) Chd1 regulates open chromatin and pluripotency of embryonic stem cells. (PubMed: 19587682)
- Stembook (2008) The pluripotent transcriptome (PubMed: 20614622)
- BMC Bioinformatics (2008) CompMoby: comparative MobyDick for detection of cis-regulatory motifs. (PubMed: 18950538)
- Cell Stem Cell (2007) On the origin of the term "stem cell". (PubMed: 18371332)