Defining ubiquitous chromatin opening element (UCOE®) molecular mechanisms of action to expedite their biotechnological applications
Dr. Michael Antoniou, Department of Medical and Molecular Genetics, King's College London.
Professor John Strouboulis, School of Cancer and Pharmaceutical Sciences, King's College London.
Dr Joe Orlando, Merck MilliporeSigma
Ubiquitous chromatin opening elements (UCOE®s) consist of one or more promoters with associated methylation-free CpG island from housekeeping genes (Neville JJ et al., Biotech Adv., 35: 557-564, 2017). UCOE®s possess dominant chromatin remodelling capabilities conferring stable and enhanced transgene expression. UCOE®s-based expression platforms for protein therapeutic biomanufacturing has been offered by Merck MilliporeSigma for many years and has seen considerable commercial success (eg see https://tinyurl.com/yyfwfhxp; Neville et al., 2017). In addition, UCOE®s provide unprecedented stability of expression from lentiviral vectors for gene therapy applications (see Neville et al., 2017; see webinar).
However, UCOE® mechanisms of function remain largely unknown. Crucially transcription factors (TFs) that mediate UCOE® activity are unidentified. This lack of basic UCOE® molecular biology knowledge has held up their refinement and further application. Thus, the aim of this application is to use interdisciplinary in silico and functional gene expression analyses to define UCOE® mechanisms of action, especially with respect to identifying the TFs that mediate their activity, which will in turn lead to the design of synthetic, compact, more versatile UCOE®s further expediting their biotechnological application.
During the course of this work the candidate will acquire a broad knowledge of basic molecular biology and biomanufacturing and gain training in a wide range of computational (bioinformatics) skills, mammalian cell culture and molecular biology (e.g. recombinant DNA, cell transfection, DNA/RNA analysis, flow cytometry, ELISA) research techniques.
The candidate will also benefit from a 3-6 month placement at the MilliporeSigma research and development facility in Bedford Massachusetts (USA).
Overall, the project will provide first-hand experience of taking a basic science investigation through to consideration for commercial scale use.
eligibility and application
Applicants must hold, or be expected to achieve, a first or high upper second-class undergraduate honours degree or equivalent (for example BA, BSc, MSci) or a Masters degree in a relevant subject. This project is funded by a 4-year BBSRC studentship, applicants should ensure they have understood the funding eligibility criteria for these studentships. Unfortunately international students are not eligible for programme funding on this project.
For more information regarding the project, please contact Dr. Michael Antoniou
Download the APPLICATION GUIDELINES here.