Epigenetic reprogramming in vivo: towards the mechanistic understanding of global DNA demethylation

Our ability to manipulate somatic cell fate is restricted by the existence of stable transcriptional networks reinforced by a complex pattern of epigenetic marks constituting the “epigenetic memory”. Although there is still no certainty as to which epigenetic marks are the key in defining and stabilising the cell fate, it has become apparent that DNA methylation is one of the key players.
In order to understand how DNA methylation patterns can be reprogrammed efficiently on a global scale we have focused our attention on biological systems where global remodelling of DNA methylation occurs naturally in a normal physiological context. It has been well documented that during mouse development, fertilised zygote and primordial germ cells (PGCs) undergo genome-wide DNA demethylation.  Recently, oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by Ten-Eleven Translocation (TET1-3) proteins has been mechanistically implicated in these instances of global methylation erasure (Guo et al, 2011, Yamaguchi et al 2013,2014). To understand the exact role of 5hmC during the global demethylation process we have 1) followed the localisation and the abundance of 5mC and 5hmC during developmental epigenetic reprogramming and 2) analysed the kinetics of the demethylation process in the absence of 5hmC formation using genetic loss of function mouse mutants. I will discuss our novel findings that reveal an alternative role for Tet driven 5mC oxidation during the reprogramming processes in vivo.


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Dr Gavin Kelsey
The Brian Heap Seminar Room