Elucidating molecular basis of ICF Syndrome with human pluripotent stem cells
The recent breakthrough in stem cell biology on somatic cell reprogramming offers invaluable tool for modeling human genetic disorders. Using fibroblasts from affected ICF syndrome patients, we have the means to generate induced pluripotent stem cell (iPSC) models. By generating DNMT3B-deficient iPSC lines, we will differentiate them to somatic stem cells and terminally differentiated cell types that are associated with ICF syndrome. It is known that DNMT3B mutations can affect genome instability and cell cycle regulation. Therefore, ICF iPSCs and its somatic derivatives will provide a powerful tool to understand the molecular function of DNMT3B in human cell physiology. Our study will shed light on the pathogenesis of ICF syndrome and to broaden potential therapeutic applicability. This proposal research will be an important step to translate stem cell research into future clinical applications.
Stem cells have emerged as a model system to understand molecular and pathogenic mechanisms underlying many human diseases such as neurodegenerative disorders (Parkinson's disease and Alzheimer's disease) and cancer and immunodeficiency. Many of these disorders are due the dysfunction of DNA methylation, a DNA modificaiton mechanism involved in regulating gene activity. Recent technology demonstrated that patient skin cells can be converted into induced pluripotent stem cells, thus generating patient specific stem cells. We propose to generate human stem cells containing genetic mutations in DNA methylation machinery. This allows to study the basic biology of a human disease due to the defects in DNA methylation. Because perturbation of DNA methylation is associated with many human diseases, we expect to learn many fundamental biology from this human stem cell study. Finally, this study will shed light on the utility of combining gene and cell therapy in curing human diseases. Our proposed research will accelerate the pace in the application of human embryonic stem cells and induced pluripotent stem cells for curing immnuodeficiency and neurological disorders, thus directly benefiting the health care of the State of California and its citizens.