New epigenetic reprogramming factors: functional testing in ES and iPS cells and development of small molecule modulators

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Stem cells and regenerative medicine hold great promise for human health and healthy ageing in the future. A number of exciting technologies have recently been developed by which the derivation of embryonic stem cells from adult cell types is now possible, albeit inefficiently. This includes the transfer of reprogramming factors into adult cells, resulting in the generation of induced pluripotent stem cells (iPS cells). This technology, however, is inefficient and a particular bottleneck appears to be the reprogramming of the epigenome. Epigenetics or the epigenome refers to all the modifications to DNA and the chromatin that are important for the function of the genome in the context of development and in the adult organism in different organs and tissues. Importantly, in germ cells and early embryos, the epigenome is reprogrammed on a genome-wide scale, so that development of a new organism and of new stem cells is possible. Work in our laboratory and that of others has revealed several features of this genome-wide epigenetic reprogramming. In collaboration with the company CellCentric, we have begun to set up a number of systematic screens for the isolation of epigenetic reprogramming factors, including those that can erase DNA methylation from the genome. The current programme of work, again with CellCentric, aims to assess the function of these new reprogramming factors in germ cells and early embryos, embryonic stem cells, and in the generation of iPS cells. CellCentric will, in particular, work on the isolation of small molecules that can alter the function of our reprogramming factors, which will then be tested in embryonic stem cells and iPS cells. The combined programme of work will shed new light on the fundamental process of epigenetic reprogramming, and provide new tools for the manipulation of stem cells and the translation into approaches to regenerative medicine and healthy ageing.