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Defining the role of NF-𝜅B during embryonic stem cell differentiation


Project Description

Mouse Embryonic stem cells (mESCs) are a useful system to probe early development. They can be maintained in a pluripotent state in culture, and differentiated using well-defined protocols to all tissue types of the embryo proper. NF-𝜅B describes a family of dimeric transcription factors that regulate the transcription of genes involved in cell fate decisions, such as cell proliferation, apoptosis, tissue immunity and repair. In the absence of stimulation, NF-𝜅B is held inactive in the cytoplasm by inhibitory I𝜅B proteins. Stimulation results in I𝜅B degradation and NF-𝜅B nuclear translocation where it modulates the expression of target genes. One of the gene targets is I𝜅B, and, following its re-synthesis, can initiate negative feedback by removing NF-𝜅B from the nucleus. Sustained pathway activation results in nuclear-cytoplasmic (N:C) NF-𝜅B oscillations due to continued cycling of inhibitor degradation, NF-𝜅B nuclear import, I𝜅B re-synthesis, and NF-𝜅B nuclear export: the frequency of these oscillations have been shown to have a role in modulating gene expression1-4. It has been suggested that NF-𝜅B may be involved in the balance between mESC pluripotency and differentiation5,6, however it is not known if, or how, the dynamics of NF-𝜅B affect this process, or what NF-𝜅B family members are involved.

Aims: We aim to fully characterise the gene expression and protein levels of NF-𝜅B family members (and inhibitors) in pluripotency, the exit from pluripotency, and following differentiation towards the three embryonic lineages. By coupling bulk cell techniques (PCR, Western blotting) and single-cell analyses (flow cytometry, immunofluorescence, state-of-the-art live-cell imaging), we will precisely define the role of NF-𝜅B during these cell-fate transitions, and whether they are modulated by defined NF-𝜅B dynamics.

Training: The IACD is an excellent multidisciplinary research environment with direct links to unique technological platforms and technical expertise, ideal for the student to learn valuable laboratory techniques and skills for their future career. The student will benefit from close interactions with both supervisors, who will be responsible for training them in all aspects of the project, including techniques such as PCR, advanced microscopy, molecular biology, and stem cell culture. Valuable experience will be gained from working within a multidisciplinary environment with regular access to journal clubs, research seminars and group meetings. IACD also runs workshops for students on Experimental Design and Statistical Analysis. Broader research training will be provided through the university’s PGR training programme and doctoral training college. IACD has a strong record in public and patient engagement, and has won awards for past events. Training is available and the student will be strongly encouraged to get involved in and lead such events.

The successful candidate should have, or expect to have, an Honours Degree at 2.1 or above (or equivalent). Candidates whose first language is not English should have an IELTS score of 6.5 or equivalent. This project is most suitable to a student with an undergraduate or Master’s degree in Developmental Biology, Pharmacology, or a related Life Sciences subject (Biology, Genetics, Biochemistry, Biomedical Sciences, Cell Biology, and Medicine).

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

To apply: please send your CV and a covering letter to Dr. David Turner () with a copy to

Applications accepted all year round.

Funding Notes

The successful applicant will be expected to provide the funding for tuition fees, living expenses, and attendance at conferences. A research bench fee of £10,000 p.a. will be levied as a contribution to laboratory consumables and research facility access. There is NO institutional funding attached to this project. Details of costs can be found on the University website.

References

1. Nelson, D. E. et al. Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 306, 704–708 (2004).
2. Ashall, L. et al. Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription. Science 324, 242–246 (2009).
3. Turner, D. A. et al. Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells. J. Cell. Sci. 123, 2834–2843 (2010).
4. Tay, S. et al. Single-cell NF-κB dynamics reveal digital activation and analogue information processing. Nature 466, 267–271 (2010).
5. Kim, Y.-E. et al. Upregulation of NF-kappaB upon differentiation of mouse embryonic stem cells. BMB Rep 41, 705–709 (2008).
6. Yang, C. et al. Opposing Putative Roles for Canonical and Noncanonical NFκB Signaling on the Survival, Proliferation, and Differentiation Potential of Human Embryonic Stem Cells. Stem Cells 28, 1970–1980 (2010).

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