Manipulating epigenetic reprogramming in vivo and its role in extraembryonic tissue function
Supervisor: Wolf Reik
Information about Project
Epigenetic reprogramming occurs in mammals in early development and leads to global erasure of repressive epigenetic marks. This reprogramming is essential for imprinting, and important for the return to pluripotency including the generation of iPS cells, the erasure of epimutations, and perhaps for the control of transposons in the genome. Following reprogramming, epigenetic marking occurs during lineage commitment in the embryo in order to ensure the stability of the differentiated state in adult tissues. Signalling and cell interactions that occur during these sensitive periods in development may have an impact on the epigenome with potentially long lasting effects. Trophoblast and placenta however have a unique epigenetic signature with relatively low levels of DNA methylation and repressive histone marks, the function of which is not known.
We have recently obtained key mechanistic insights into global demethylation during transition to naïve pluripotency, which involves dual regulation of UHRF1 and of H3K9me2 through protein stability. Hence most of the mechanistic components for global demethylation are now known, and this PhD project therefore aims to manipulate these systems in pluripotent cells and in mice in order to disable genome-wide demethylation. You will investigate the effects of impaired reprogramming in vitro and in vivo including on trophoblast and placental development. You will carry out advanced epigenome sequencing studies and computational analysis including in single cells and with collaborators also on human embryos. You will be part of an enthusiastic, collaborative and highly motivated team which is embedded in one of the largest epigenetics and chromatin research communities in Europe.
Recent references: Branco et al 2016 Developmental Cell, Angermueller et al 2016 Nature Methods, von Meyenn et al 2016 Molecular Cell.
For further information, please do not hesitate to contact me:
Telephone: +44 (0)1223 496336