Every cell in the body carries a chemical memory—the epigenome—that tells it what kind of cell to be, and this memory must be wiped clean in early embryos so that cells can become any tissue type. The problem is that scientists do not fully understand how this erasure happens, nor how cells then quickly re-establish new memories to guide their development into specific organs. This research programme tackles three gaps: how the cell disables a key protein (UHRF1) to trigger global memory erasure, how certain genes are protected from being silenced so they can later activate, and how other genes are deliberately repressed to prevent cells from taking the wrong path. The work is fundamental science—it asks how cells decide their identity, a question with no immediate practical application. However, similar fundamental discoveries about epigenetic reprogramming have already enabled the creation of induced pluripotent stem cells (iPS cells), which are now used to model diseases in the lab. Deeper understanding of memory erasure and priming could eventually improve how stem cells are guided to form specific tissues for regenerative medicine.
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Epigenetic memory needs to be globally reprogrammed in the early mammalian embryo for cells to attain broad developmental potency including naïve pluripotency. Exit from pluripotency in turn requires rapid establishment of epigenetic memory in the form of epigenetic priming. This involves both ‘activating priming’ whereby lineage specific genes are protected from repressive marking to safeguard their future transcriptional activation during tissue and organ development, and ‘repressive priming’ by which genes of a different lineage are suppressed. These large-scale dynamics raise fundamental questions about the impact of epigenetic memory on pluripotency and differentiation, which we address in this research programme. First, we will attempt to disable global demethylation in vitro and in vivo by manipulating the epigenetic coordinator UHRF1 at the transcriptional and posttranscriptional levels. Second, using genetic and epigenetic manipulation we will determine the mechanisms and downstream consequences on lineage and tissue development of ‘activating priming’ factors we have recently identified. Third, we will investigate the role and targets of ‘repressive priming’ and epigenetic heterogeneity in cell fate decisions and lineage development. New insights gained into memory erasure and epigenetic determinants of cell fate will illuminate and guide strategies for using ES, iPS, and multipotent stem cells in regenerative medicine.
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