Reprogramming the epigenome for stem cells and in ageing

Theme: World-Class Underpinning Bioscience

Epigenetic information in the genome is important for normal development and its deregulation can be associated with various diseases. Epigenetic information is generally stable in differentiated cells in the adult organism, though it degrades during ageing. However in germ cells, early embryos, naïve embryonic stem cells and iPS cells genome-wide reprogramming of epigenetic information takes place. Epigenetic reprogramming is associated with the return of the genome to pluripotency or potentially totipotency, the erasure of epimutations, resetting parental imprints, and possibly the repression of retrotransposons in the germline. Epigenetic reprogramming is also critical for experimental reprogramming such as cloning by nuclear transfer, cell fusion, and iPS cell generation. Erasure of epigenetic information in the germ line is incomplete however and this may result in transgenerational epigenetic inheritance. Single cell DNA methylation sequencing has also revealed substantial epigenetic heterogeneity between cells, which may be associated with transcriptional and functional diversification of cells during development or ageing. Predictable epigenetic changes occur during the ageing process raising the question of whether there is an epigenetic programme that might underlie aspects of ageing and functional decline.

You will be working in an internationally leading lab that studies the mechanisms and functional consequences of epigenetic reprogramming. You will study the molecular pathways of reprogramming especially of demethylation of DNA which includes passive and active demethylation. Passive demethylation can occur by regulation of Dnmt1 and Uhrf1 including by cell signaling principles. Active demethylation occurs by oxidation of methylcytosine (5mC) to hydroxymethylcytosine (5hmC), formylcytosine (5fC), and carboxylcytosine (5caC) by the TET enzymes or by deamination by AID/APOBEC enzymes and base excision repair. You will be using mouse knockout and cell models, or biochemical approaches, to study these pathways. Our approaches include epigenomics, bioinformatics, cell signalling, and modelling which you will have the opportunity to engage with, including single cell epigenomics through the affiliated Single Cell Genomics Centre (http://www.sanger.ac.uk/research/projects/singlecellcentre, at the nearby Sanger Institute). The functional consequences of manipulating reprogramming pathways for normal development, ageing, pluripotency and iPS cell generation will also be investigated. You will be joining an enthusiastic and collaborative team of students and postdocs embedded in one of the largest programmes of Epigenetics and Nuclear Dynamics science within Europe.