The Role of Higher-Order Chromosome Structure in Pluripotency and Reprogramming
The development of methods to "reprogram" cells of adults such as skin cells to cells resembling embryonic stem (ES) cells is a major breakthrough in stem cell biology. ES cells have the potential to develop into any type of tissue. This means that skin cells taken from a patient could be induced to become ES-like cells and then used to replace virtually any diseased or damaged tissue in that same individual. However, reprogramming is still an inefficient process, which limits its potential application in cell transplantation therapy and studies of disease. Genes reside on chromosomes in the cell nucleus, and the manner in which chromosomes are packaged and positioned in the nucleus—the nuclear architecture—is now recognized to be important in regulating gene expression and cell identity. The nuclear architecture is different between somatic cells and stem cells. Understanding how the nuclear architecture change during reprogramming, and how interactions among chromosomes regulate pluripotency is very important for understanding the mechanisms of reprogramming. In this study we will undertake biochemical, computational, molecular investigations to understand the role and mechanisms of changes in nuclear architecture in reprogramming to pluripotent cells. These studies should help us to develop novel strategies to make reprogramming more efficient so that cells can be generated on a large scale for use in regenerative medicine, individualized medicine and drug discovery.
California is the most populous state in the nation. Each year numerous patients in California suffer from diseases, such as Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, multiple sclerosis, diabetes and cancer, without a cure. Since many of these diseases are chronic and require life-time treatment, the medical costs incurred are a huge burden for patients’ families and for the society. Stem cell treatments offer hope for many patients suffering from currently incurable diseases. The development of technology to reprogram patient-specific skin cells into induced pluripotent stem (iPS) cells moves us one step closer to developing stem cells suitable for cell replacement therapy and drug screening. Stem cells generated from a patient could potentially be used to replace that individual’s diseased or damaged tissues while avoiding an immune response. Patient-specific iPS cell lines can also be used for drug discovery and toxicology studies. Since the mechanisms of reprogramming are largely unclear, being able to define the mechanisms underlying iPS cell induction will be important before iPS cells can be used effectively for therapy to address some of the most devastating healthcare issues in our state. California is a leader in stem biology research, and significant economic benefits, including job creation and revenue associated with application of stem cell technologies and drug discoveries, could accrue to the State of California and its citizens.