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The correct regulation of transcription is crucial for development and homeostasis, with misregulation causative for human diseases. In addition to the primary enhancer that activates transcription of a nearby gene, additional ‘shadow’ enhancers exist that direct similar expression patterns to the primary enhancer. These seemingly redundant enhancers are commonly associated with developmental genes, including those related to human disease. Another feature of enhancers is that around two thirds are transcribed in organisms ranging from worms to humans, although the function of enhancer RNA (eRNA) transcription is poorly understood. The aim of this project is to determine how transcription factor inputs and enhancers define transcription dynamics during embryonic development. To address this research aim we will leverage the strengths of the Drosophila embryo, including its genetic tractability, ease of CRISPR genome editing, short life cycle and suitability for single molecule imaging. We will focus on a key developmental gene (tailup, tup) that is activated by a primary enhancer and two shadow enhancers. Firstly, we will use live MS2 imaging of transcription to determine the transcription dynamics of embryos carrying single tup enhancers or combinations of them. This will reveal the contribution of each enhancer to the transcriptional output. Secondly, we will use CRISPR genome editing to disrupt eRNAs for the different enhancers and determine the effect on tup transcription dynamics. Thirdly, we will use optogenetics to define the critical time window when key transcription factors, and the upstream signal that activates these transcription factors, are required. Overall, these findings will allow us to determine how transcription factors and eRNAs control each enhancer’s ability to activate transcription in real-time as the embryo is developing. Moreover, the findings will provide a framework for understanding how perturbation of enhancer function leads to misregulation of transcription causing developmental anomalies and human disease.
Relevant links
https://research.manchester.ac.uk/en/persons/magnus.rattray
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
References
Forbes Beadle, L., Love, J.C., Shapovalova, Y., Artemev, A., Rattray, M. and Ashe, H.L. (2023). Modelling global mRNA dynamics during Drosophila embryogenesis reveals a relationship between mRNA degradation and P-bodies. PLOS Biol 21:e3001956.
Hoppe, C., Ashe, H.L. (2021). Live imaging and quantitation of nascent transcription using the MS2/MCP system in the Drosophila embryo. STAR Protocols 2, 100379.
Hoppe, C., Ashe, H.L. (2021). CRISPR-Cas9 strategies to insert MS2 stem-loops into endogenous loci in Drosophila embryos. STAR Protocols 2, 100380.
Bowles, J.R., Hoppe, C., Ashe, H.L., and Rattray, M. (2021). Scalable inference of transcription kinetic parameters from MS2 time series data. Bioinformatics 38, 1030.
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