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.
Research in our lab focuses on understanding the transcriptional and epigenetic reprogramming events that take place in normal mammalian development, and on uncovering novel axes of gene regulation. Particularly, we are interested in the function of transposons which have been greatly understudied in development, despite making up 50% of our genomes. Our recent research(1-2) indicates that certain transposons are expressed and play essential roles during early mouse development, and we are particularly interested in dissecting how transposon regulation is important during embryogenesis.
We employ a combination of candidate and genome-wide approaches in ESCs, CRISPRi/a technology, bioinformatics, high-resolution imaging and molecular embryology to understand 1) mechanisms of transposon regulation and 2) the implications of transposon expression for ZGA, cell fate, embryogenesis and disease.
Projects in the lab are focused on several exciting aspects of transposon regulation:
i) Role and regulation of ERVL transposons in the totipotency-to-pluripotency transition in early embryos and ESCs(1-4)
ii) Dissecting novel instances of transposon function in cell fate transitions
iii) Exploring transposon mis-regulation in disease
The Chromatin and Development Group is a recently-established Lab within the Epigenetics division of the MRC London Institute of Medical Sciences (MRC LMS) – a world-class research institute closely associated with Imperial College. The successful student will be funded by a prestigious LMS 3.5 year PhD studentship.
This project is directly funded for UK or EU students only.
If successful the student would receive full tuition fee payments for 3.5 years as well as a tax free stipend amounting to £21,000pa paid in monthly installments for the duration of their studentship.
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