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Investigating the role of membrane transporters in early development


Project Description

This is a joint project between the Chromatin and Development and the Drug Transport and Tumour Metabolism groups within the MRC LMS. The aim of this project is to dissect the role of membrane transporters in regulating the metabolic changes that take place during early embryonic development.

In early development, a fertilized zygote proceeds through a series of 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), which have become valuable tools for understanding development and regenerative medicine. Since many pathways active during development are hijacked by cancer cells, their study has also given us insight into important processes in cancer.

Recently, it has become clear that major metabolic changes take place during different stages of early embryo development, and that these metabolic shifts may play an important role in driving the epigenetic rewiring that determines pluripotency. How these metabolic changes are regulated, however, is still unclear. Since polar metabolites are not membrane permeable, membrane transporters are essential to regulate both their uptake and release across the plasma membrane, and also their transfer between different cellular compartments. With more than 400 solute carrier (SLC) transporters encoded within the genome, different cell types are able to tailor their transporter expression patterns to shape metabolism according to their functional requirements.

The goal of this project is to uncover how the expression of SLC family transporters changes during the initial stages of early development, and to determine how these expression patterns influence the metabolic changes taking place during development. We employ a combination of candidate and genome-wide approaches in mouse and human ESCs, CRISPRi/a technology, bioinformatics, high-resolution imaging and molecular embryology. These techniques are combined with state-of-the-art metabolomics and stable isotope labelling to permit sensitive analysis of metabolic changes that underlie distinct stages of development.

The successful PhD student will model distinct pre- and peri-implantation stages of development in culture using established mouse and human ESC lines and culture conditions, and employ GC-MS metabolomics combined with stable isotope labelling to observe the metabolic differences between these stages. Based on bioinformatic analysis of transporter expression patterns, they will use CRISPR/Cas9 technology to perturb the expression of key transporters-of-interest, and combine this with pharmacological approaches to investigate their role in development and pluripotency. The student will benefit from the complementary expertise of two labs within the LMS and will be welcomed as a fully integrated member of both groups. These studies will shed light on the importance of SLC proteins and SLC-driven metabolic changes in early development, and may inform our understanding of their roles in pathophysiological contexts such as cancer.

Links
https://lms.mrc.ac.uk/research-group/chromatin-and-development/
https://lms.mrc.ac.uk/research-group/drug-transport-tumour-metabolism/

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.

References

1. Percharde M, Lin C-J, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X, Ramalho-Santos M. (2018). A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity. Cell. 174, 391-405.

2. Fets L, Driscoll PC, Grimm F, Jain A, Nunes PM, Gounis M, Doglioni G, Papageorgiou G, Ragan TJ, Campos S, dos Santos MS, MacRae JI, O’Reilly N, Wright AJ, Benes CH, Courtney KD, House D, Anastasiou D. (2018). MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG. Nat Chem Biol 14, 1032–1042.

3. Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M, Bomze D, Elena-Herrmann B, Scherf T, Nissim-Rafinia M, Kempa S, Itskovitz-Eldor J, Meshorer E, Aberdam D, Nahmias Y. (2015). Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 3, 392-402

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