Epigenetic processes regulate gene transcription states during cellular differentiation, playing key roles in the maintenance of pluripotency and differentiation. Epigenetic alterations are common in diseases such as in cancer and cognitive disorders. Understanding the mechanisms by which epigenetic states are inherited and propagated is of fundamental importance, and will help in the development of biomarkers for screening as well identification of targets for disease treatment.
DNA methylation remains the best-characterized epigenetic process. XX pluripotent stem cells (Embryonic Stem (ES) and induced Pluripotent Stem (iPS) cells) display genome-wide hypomethylation relative to XY stem cells but the mechanisms are unknown. This proposal will elucidate the pathways responsible. Irradiation Microcell-Mediated Chromosome Transfer (XMMCT) will be used to identify the critical region(s) of the X chromosome involved. In parallel and as an alternative approach, candidate X-linked genes will be over-expressed in XY ES cells to identify the factors responsible for global hypomethylation. Further insight will be provided using protein interaction screens using epitope-tagged versions of all active Dnmts as well as the known regulators URHF1 and Dnmt3L in XX and XY ES cells. The role of XX-induced hypomethylation in cellular reprogramming will be investigated by using different cell types from Oct4-GFP transgenic mice to examine whether iPS efficiency is affected by cells with a greater propensity to lose DNA methylation. Together these aims will elucidate the signals necessary to maintain global genomic DNA methylation. Aberrant loss is an important hallmark and contributor of disease that could be used for disease diagnosis and treatment. It could also be exploited to help improve the efficiency of cellular reprogramming for regenerative medicine.
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