Differentiated normal cell identity and epigenetic barriers to trans-differentiation and reprogramming

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Cellular identity is defined by the expression of certain genes that result in the production of specific proteins. Typically, gene expression is known to be regulated by epigenetic mechanisms. Pluripotent stem cells can be converted to a specialised cell identity in a process known as differentiation. Contrariwise, somatic cells can be reprogrammed back to cells with a stem-like identity, also called induced pluripotent stem cells (iPSCs), by using a subset of transcription factors. A degree of plasticity thus exists that allows cells to switch between cell identities. Controlling this process remains challenging as cells often retain some epigenetic memory of their previous origin, and therefore may resist any change to their identity or revert to their original cell origin. Therefore, current limitations of iPSCs technology include low reprogramming efficiency, tumour development and spontaneous differentiation. Elucidating the role of epigenetic mechanisms in governing cell identity and providing a cell with its memory will help advance the applications of stem cell research in regenerative medicine, disease modelling and drug discovery. Previously, it has been shown that the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes is associated with active gene transcription and plays an essential role during cell conversion. Namely, during iPSC reprogramming, 5hmC enrichment and TET activity facilitate DNA demethylation and transcriptional reactivation of pluripotency. Consequently, cells that lack TET expression cannot be reprogrammed to iPSCs. Additionally, global levels of 5hmC have been identified to differ between distinct tissue and cell types. Thus, 5hmC might act as a key intermediate essential to determining cell identity. It is therefore likely that genomic 5hmC distributions could be used as signatures of cell identity during cell conversion. The general objective of this project is to investigate how a cell knows what it is. More specifically, the aim is to elucidate the role of 5hmC in the epigenetic mechanism that establishes and maintains cell identity during cellular reprogramming. This will be achieved by identifying the role of 5hmc-mediated DNA demethylation in driving cell identity, determining how histone modifications and 5hmC come together to enable cell reprogramming and by establishing mathematical models to describe the interplay between gene expression, DNA methylation and histone modifications during cell conversion.