PhD Projects on offer
Mechanisms and functions of epigenetic reprogramming in the mammalian embryo
Supervisor: Wolf Reik
Epigenetic marks such as DNA methylation and histone modifications are generally stable in somatic cells, but are reprogrammed on a genome wide scale in germ cells and early embryos. Approximately 80% of all the DNA methylation in the genome, for example, is erased in germ line cells (primordial germ cells). Reprogramming is important for imprinting, the return of the embryonic genome to pluripotency, the erasure of acquired epimutations, and probably also for the control of retrotransposons. Hence understanding reprogramming is crucial for insights into transgenerational epigenetic inheritance, the immortality of the germ line, and in order to harness the full potential of experimentally induced pluripotency (in iPS cells). Reprogramming is also important so that early lineage commitment to the embryonic and extraembryonic lineages, respectively, can occur appropriately. You will join an interactive and collaborative team and will use epigenomic profiling techniques based on high throughput sequencing (in our in house epigenomics sequencing facility) in order to understand the dynamics of reprogramming on a genome wide scale together with discovering connections between epigenetic marks as well as with the transcriptome. Some of the candidate mechanisms for erasure of DNA methylation, which include modification of methylcytosine (eg by deamination or hydroxylation) coupled with base excision repair, are also being elucidated. You will be analyzing the expression of key candidate factors and use knockout mice in which pathways that modify methylcytosine and those that are involved in DNA repair are mutated, in order to assess the effects in vivo on reprogramming. You may also use the iPS cell system in order to test the role in experimental reprogramming of selected epigenetic reprogramming factors.
For recent publications see Nature 447, 425 (2007), Nature Genet. 40, 971 (2008), Nature Cell Biology 10, 1280 (2008), Cell 136, 629 (2009), Nature Rev. Mol. Cell. Biol. 10, 526 (2009), Nature 463, 1101 (2010).
