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(MRC DTP) Regulatory chromatin and transcriptional networks impacting on embryonic stem cell differentiation


Project Description

Embryonic stem cells (ESCs) can give rise to all of the cells in the body so a detailed understanding of how they commit to other cell fates is fundamentally important to understanding both normal human developmental processes and how developmental defects arise. It also has the potential to inform therapeutic approaches using regenerative medicine. Reciprocally, in diseases like cancer, cells can revert to earlier embryonic fates as exemplified by our work in oesophageal adenocarcinoma (Rogerson et al., 2019) effectively reversing the state transitions. Currently we know a lot about the pluripotent state and the differentiated cell states (eg see Yang et al., 2014) but very little about how cells transition to these states. We have recently uncovered an important regulator of an early cell fate transition, the transcription factor ZIC3 (Yang et al., 2019) but we do not know how this contributes to gene activation. The aim of this project is to understand how ZIC3 and other transcription factors work together during the transition phase of embryonic stem cell differentiation as cells become committed to differentiate. We will test how combinations of transcription factors work together in a temporal manner to activate and remodel the chromatin landscape and ultimately drive gene transcription. We will use genome-wide approaches to study regulatory factor function. Genome-editing techniques based on CRISPR-Cas9 approaches will be used to test the functionality of the discovered regulators and regulatory element. We will couple our analysis to single cell transcriptomic and epigenetic approaches which will enable us to uncover patterns among the heterogonous behaviour of the transitional cell populations. The project will provide training in a wide range of molecular, cell biology and biochemical skills. In addition, genome-wide techniques such as RNA-seq, ChIP-seq and ATAC-seq will be used in conjunction with advanced bioinformatics analysis.

https://www.research.manchester.ac.uk/portal/andrew.d.sharrocks.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

(1) Rogerson C., Britton, E., Withey, S., Hanley, N., Ang, Y. and Sharrocks, A.D. (2019) Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state. Genome Research. 29(5):723-736.
(2) Yang, S-H., Kalkan, T., Morissroe, C., Marks, H., Stunnenberg, H., Smith, A., and Sharrocks, A.D. (2014) Otx2 and Oct4 drive early enhancer activation during ES cell transition from naïve pluripotency. Cell Reports. 7:1968-81.doi: 10.1016/j.celrep.2014.05.037.
(3) Yang, S-H., Andrabi, M., Biss, R., Baker, S.M., Iqbal, M. and Sharrocks, A.D. (2019) ZIC3 controls the transition from naïve to primed pluripotency. Cell Reports. 27:3215-3227.

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