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Understanding the gene regulatory landscape of embryonic stem cells and cancer cells


Project Description

Cell identity is ultimately determined through decoding the genome through the action of gene regulatory mechanisms. In particular, sculpting of the chromatin landscape to reveal unique configurations of gene regulatory elements in each cell type is a major driver of cell identity. Embryonic stem cells (ESCs) represent a dynamic environment in which to study this process and have obvious therapeutic potential in regenerative medicine. We have uncovered several transcription regulators that drive the initial stages of ESC differentiation [1,5]. However, the mechanisms through which they interact with and control the regulatory chromatin environment are not known. Reciprocally, cancer can be viewed as a reversal of the cellular differentiation process, and our recent work on oesophageal adenocarcinoma provides a key demonstration of this type of event [2]. We have begun to understand how transcription factors drive cancer formation through acting on the regulatory chromatin landscape [2,4]. However, it is not clear how different transcription factors contribute to this remodelling. Furthermore, it is unclear how cellular signalling pathways impact on the activity of these regulatory events although we know they play critical roles during normal differentiation and changed roles during tumourigenesis.
Projects are available to further our understanding of how transcription factors, either individually or in combination, interact with the genome to initiate and maintain the activities of gene regulatory elements, in the context of both normal differentiation and also during cell fate changes in cancer. This may reveal new therapeutic opportunities.

Training/techniques to be provided:
Training will be provided in basic biochemical, molecular and cell biological approaches. This will involve cell culture and manipulation using CRISPR technologies, western blotting, recombinant protein production, nucleic acid isolation (eg RNA) and microscopy approaches to image dynamic regulatory events at the single cell level. However, it is important to take genome-wide views of the regulatory events, so bioinformatics training will be provided to analyse and integrate complex datasets. Publically available datasets will be used alongside those generated by the student from a range of possible approaches including RNA-seq, ChIP-seq, ATAC-seq, PRO-seq, Hi-seq, and Capture-C which capture a range of regulatory events ranging to 3D regulatory element rearrangement through to the production of the RNA transcripts.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum first class honours degree (or equivalent) in a related area / subject. Candidates with laboratory experience in molecular and cell biology techniques are encouraged to apply. Additional training in bioinformatics approaches is desirable. A keen interest in studying gene regulatory mechanisms is essential.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy 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] 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.
[2] 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.
[3] Baker, S.M., Rogerson, C., Hayes, A., Sharrocks, A.D. and Rattray, M. (2019) Classifying cells with Scasat, a single-cell ATAC-seq analysis tool. Nucleic Acids Research. 47 (2), e10.
[4] Britton, E., Rogerson, C., Mehta, S., Li, Y., Fitzgerald, R., Ang, Y., and Sharrocks, A.D. (2017) Open chromatin profiling identifies AP1 as a transcriptional regulator in oesophageal adenocarcinoma. Plos Genetics, 13(8):e1006879.
[5] 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

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