"Transcription factor-based reprogramming has enabled the generation of induced pluripotent stem cells (iPSCs). IPSCs can be used in disease modelling and derivation of rejection-free mature cell types for cell-replacement therapies. Proof-of-principle studies show that a number of genetic, complex, and malignant diseases can benefit from such cell-based therapies. Despite their immense potential, technical obstacles remain in the generation of iPSCs. This project is aimed at generating tools to overcome these obstacles by elucidating the molecular mechanisms of reprogramming. The fundamental mechanisms by which somatic cell identity gets replaced by pluripotent cell identity during reprogramming are poorly defined. Cellular identity is largely controlled by chromatin-based epigenetic mechanisms and while there is increasing knowledge about the distinct epigenetic states before and after reprogramming, the role of key chromatin modifier genes in reprogramming remains largely unexplored.
Previous research has indicated that it is possible to identify key chromatin-based modulators of reprogramming and use this knowledge to increase reprogramming efficiency and replace exogenous factors with chemical compounds (Onder et al. 2012). To extend these studies further, identify novel chromatin-based regulators of reprogramming, and understand the molecular mechanisms of these regulators, this project will: (1) elucidate the mechanism by which inhibition of histone methyl-transferases Suv39H1 and Setd2 enhances reprogramming, and (2) identify histone demethylases that act as positive or negative regulators of reprogramming. This project will not only contribute to our understanding of the molecular basis of reprogramming, but also proposes to use that knowledge to facilitate efficient generation of iPSCs which will have significant clinical uses in the near future."
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