PhD Projects on offer
Stem cells in the early placenta: Mechanisms underlying self-renewal and differentiative potency of this unique stem cell population
Supervisor: Myriam Hemberger
We are interested in the epigenetic regulation of cell fate decisions in early mammalian development and their impact on the potency of stem cells derived from the early embryo. Specifically, we are interested in stem cell populations that exist in the mouse and human placenta, and the mechanisms that maintain their developmental potency and self-renewal. We have recently shown that a key transcription factor, Elf5, establishes a critical transcription factor network that is essential for trophoblast lineage commitment, trophoblast stem cell maintenance and restriction of these stem cells to the placenta through epigenetic repression of Elf5 in embryonic cells. We are interested in the transcriptional and signalling mechanisms required to maintain the activity of this transcriptional network. The studentship project builds on this novel concept and will investigate how signalling pathways interact with the epigenome to establish this critical stem cell population. Mechanistic studies will then determine whether manipulating epigenetic modifications (such as DNA methylation) at key target genes can reprogram stem cell fate and allow a switch between stem cell types. Insights into this regulation are important to understand the epigenetic control of trophoblast and embryonic stem cell determination, and will help us understand why epigenetic disruptions (including those occurring in human ART) are particularly detrimental for trophoblast differentiation and placental function, and hence the outcome of pregnancy.
The studentship project will provide critical insights into epigenetic and developmental mechanisms in the field of stem cell biology and early cell fate determination. It will combine a range of state-of-the-art techniques including epigenomics, embryology, and computational biology in order to unravel the key events in early lineage commitment. These approaches have great relevance to stem cell biology, reprogramming, regenerative medicine, mammalian reproduction and developmental biology. The student will greatly benefit from the expert environment in the field of Epigenetics and Developmental Genetics and from the Epigenomics Facility at the Babraham Institute.
Recent, relevant publications:
Senner C.E. and Hemberger M. Regulation of Early Trophoblast Differentiation - Lessons from the Mouse. Placenta, 2010 Aug 24.
Hemberger M., Udayashankar R. Tesar P., Moore H. and Burton G. (2010). ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta. Hum. Mol. Gen., 19: 2456-2467.
Hemberger M. (2010). Genetic-epigenetic intersection in trophoblast differentiation: Implications for extraembryonic tissue function. Epigenetics, 5: 1-6.
Hemberger M., Dean W. and Reik W. (2009). Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington’s canal. Nature Reviews Mol. Cell Biology, 10: 526-537.
Ng R.K., Dean W., Dawson C., Lucifero D., Madeja Z., Reik W. and Hemberger, M. (2008). Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nature Cell Biology, 10: 1280-1290.
