Deciphering and overcoming epigenetic erosion at imprinted loci in mouse and human naive pluripotent stem cells

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During the routine petri dish culture of naïve pluripotent stem cells it was found that these acquire errors in a group of genes named imprinted. Naïve pluripotent stem cells are cells that represent the very earliest stage of embryonic development, and have the ability to self-replicate exactly or to change into any cell type in the body. Imprinting is a phenomenon that leads to genes being expressed in a parent of origin specific manner. This process involves modifications, DNA methylation and histone methylation, at regulatory regions of imprinted genes that affects their expression. These imprint marks are naturally erased and established in the germline of the parents and are subsequently maintained in all the other cells (soma) from the fertilized egg till adulthood. Abnormally, these imprints are erased in the routine petri dish culture of naïve pluripotent stem cells hindering the potential of these cells. My group has recently discovered a gene, Impera, that potentially directs the observed removal of imprints at imprinted genes. Now we want to define mechanistically how Impera works and to define strategies that prevent Impera from inducing imprint erasure. Achieving these goals will lead to a fundamental discovery in developmental biology, the first identified gene capable of mediating imprint erasure, and to the prevention of imprint erasure in the cultures of both mouse and human naïve pluripotent stem cells. In the medical context, appropriate imprinting is important for normal development. Human diseases involving inappropriate/lack of imprinting include Angelman syndrome and Prader-Willi syndrome. Thus, understanding mechanistic how imprint erasure occurs may uncover pathways and processes that will enhance our understanding of pathological processes. Naïve pluripotent stem cells are also widely used as a platform for early developmental research, with much investment being focussed on both understanding how cells maintain their naïve state and how they commit to becoming specific cell types. The proposed research will provide insights into how we might be able to stabilise stem cells in this naïve state, providing more stable stem cell platforms for use as a research tool, in drug discovery programmes and in regenerative medicine applications. Our research group has a strong track record in stem cell biology and has the necessary expertise to successfully complete this important project. Further, working within the Cambridge Stem Cell Institute puts us in a strategically strong position, with close collaborators including Dr Kevin Chalut. An expert in the physical biology of pluripotency and differentiation which together with my lab developed a novel hydrogel protocol (manuscript in preparation) which supports naïve pluripotent stem cell self-replication. This may prove a very useful tool in our aim to generate naïve pluripotent stem cells free of imprint errors