In early development, a single fertilized zygote proceeds through a series of cleavage steps to develop into a multicellular blastocyst. The cells of the blastocyst are capable of generating all adult cell types, a phenomenon known as pluripotency. The inner cell mass (ICM) of the blastocyst can moreover be cultured in vitro as pluripotent embryonic stem cells (ESCs). ESCs have become invaluable tools for understanding development and for regenerative medicine. With 1 in 8 couples experiencing infertility in the UK, it is ever more important to understand the factors contributing to healthy embryo development. Furthermore, developmental pathways important for maintaining an undifferentiated state are often hijacked in diseases such as cancer.
How the early embryo develops into a pluripotent blastocyst involves a remarkable reprogramming of cellular transcriptional networks, epigenetic modifications, and signalling pathways. There is still much to be understood about how these layers of regulation contribute to normal embryo development, or may be perturbed in disease. Research in our lab focuses on understanding the reprogramming events that take place in development, and on uncovering novel axes of gene regulation. Particularly, we are interested in the function of transposable elements (TEs), which have been greatly understudied in development, despite making up 50% of our genomes. Recent research(1-4) indicates that certain TEs are expressed and play essential roles during mouse and human development, and we are particularly interested in dissecting how TE regulation is important during embryogenesis.
In this project, we will investigate the regulatory dynamics, mechanism, and functional importance of TE expression in development. A particular family of TEs, ERVL retrotransposons, are highly and specifically activated at the early cleavage stage of mouse and human development, and in 2 cell-like cells within mESC culture(1,3-4). The 2-cell stage not only encompasses the essential process of Zygotic Genome Activation (ZGA) but also the phenomenon of totipotency, the highest degree of developmental potential. We will employ a combination of candidate and genome-wide approaches in ESCs, CRISPRi/a technology, bioinformatics, high-resolution imaging and molecular embryology to understand 1) the mechanisms of TE regulation during development and 2) the implications of TE expression for ZGA, totipotency and embryogenesis.
This project is competition funded for students worldwide.
If successful the student would receive full tuition fee payment for 3.5 years as well as a tax free stipend amounting to £21,000pa paid in monthly instalments for the duration of their studentship.
Whilst Overseas Students are eligible, funding is more limited so only exceptional OS students will be considered.
Percharde M, Lin CJ, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X and Ramalho-Santos M (2018) A LINE1-Nucleolin partnership regulates early development and ESC identity. CELL https://doi.org/10.1016/j.cell.2018.05.043
Percharde M, Wong P and Ramalho-Santos M (2017) Global hypertranscription in the mouse embryonic germline. CELL REPORTS https://doi.org/10.1016/j.celrep.2017.05.036
Macfarlan TS, Gifford WD, Driscoll S, Lettieri K, Rowe HM, Bonanomi D, Firth A, Singer O, Trono D, Pfaff SL (2012) Embryonic stem cell potency fluctuates with endogenous retrovirus activity. NATURE https://doi.org/10.1038/nature11244
Hendrickson PG, Doráis JA, Grow EJ, Whiddon JL, Lim JW, Wike CL, Weaver BD, Pflueger C, Emery BR, Wilcox AL…et al (2017) Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. NATURE GENETICS https://doi.org/10.1038/ng.3844