Developing a pipeline for rapid optimisation of transcriptional expression regulation

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences


A key challenge in engineering biological systems is the development of re-usable, precise and tunable gene expression control elements. Currently, developing these systems requires expensive and time-consuming experiments based on trial-and-error. This is particularly problematic for applications requiring complex systems with multiple co-regulated components or systems that use components obtained from non-model microorganisms.

This project will develop tools to systematically characterise transcriptional control elements, uncovering their design rules to enable re-use of these control elements in alternative hosts and genetic contexts.

Transcriptional regulation in prokaryotes is achieved primarily through the binding of transcription factors (TFs) to a promoter. Each TF has a specific binding preference, which determines its function (activator or repressor) and the location of its binding site(s) within a promoter. Knowing the biophysical binding preferences of TFs, hence, enables computational prediction of the regulatory logic and the transcriptional activity of any given promoter1,2. Currently, however, the biophysical binding preferences are known for only a handful of TFs, meaning that we cannot easily exploit heterologous TFs in bioengineering.

In this interdisciplinary project, the student will utilize a range of molecular/synthetic biology, microbiology, and biophysical approaches to: (i) develop an experimental and data analysis pipeline that can determine the binding preferences of any given TF; (ii) unravel design rules of activators; (iii) use the pipeline to study the evolutionary rules governing how TFs adapt to heterologous hosts. As such the student will acquire skills that are highly relevant for future careers in the molecular biology and microbiology, biotechnology, biopharmaceutical, industrial biotechnology and related industries.

Achieving these objectives will enable researchers to rapidly characterize the function (i.e. binding preference) of any desired TF, incorporate that TF into any desired regulatory network, and computationally predict promoter sequences that would contain a desired regulatory logic and result in desired transcriptional expression levels.

Planned Impact

The 2016 UK Roadmap Bio-design for the Bio-economy highlighted the substantial impact that synthetic biology can bring to the UK and global economies by developing: frontier science and technology; establishing a healthy innovation pipeline; a highly skilled workforce and an environment in which innovative science and businesses can thrive. Synthetic biology promises to transform the UK Bio-economy landscape, bringing bio-sustainable and affordable manufacturing routes to all industrial sectors and will ensure society can tackle many contemporary global Grand Challenges including: Sustainable Manufacturing, Environmental Sustainability Energy, Global Healthcare, and Urban Development. Whilst synthetic biology is burgeoning in the UK, we now need to build on the investments made and take a further lead in training next generation scientists to ensure sustained growth of a capable workforce to underpin the science base development and growth in an advanced UK bio-economy.
This training provided by this CDT will give students from diverse backgrounds a unique synthesis of computational, biomolecular and cellular engineering skills, a peer-to-peer and industrial network, and unique entrepreneurial insight. In so doing, it will address key EPSRC priority areas and Bioeconomy strategic priorities including: Next-generation therapeutics; Engineered biomaterials; Renewable alternatives for fuels, chemicals and other small molecules; Reliable, predictable, and scalable bioprocesses; Sustainable future; Lifelong health & wellbeing.
Advances created by our BioDesign Engineering approach will address major societal challenges by delivering new routes for chemical/pharma/materials manufacture through to sustainable energy, whilst providing clean growth and reductions in energy use, greenhouse gas emissions and carbon footprints. Increased industry awareness of bio-options with better civic understanding will drive end-user demand to create market pull for products. The CDT benefits from unrivalled existing academic-industry frameworks at the host institutions, which will provide direct links to industrial partners and a direct pathway to early economic and industrial impact.

This CDT will develop 80-100 next-generation scientists and technologists (via the funded cohort and wider integration of aligned students at the three institutions) as adept scientists and engineers, instilled with technical leadership, who as broadly trained individuals will fill key skills gaps and could be expected to impact internationally through leadership roles in the medium term. Importantly the CDT addresses key skill-gaps identified with industry, which are urgently required to create and support high value jobs that will enable the UK to compete in global markets. Commercialisation and entrepreneurship training will equip the next generation of visionaries and leaders needed to accelerate and support the creation of new innovative companies to exploit these new technologies and opportunities.

The UK government identified Synthetic Biology as one of the "Eight Great Technologies" that could be a key enabler to economic and societal development. This CDT will be at the forefront of research that will accelerate the clean growth agenda and the development of a resilient circular bioeconomy, and will align with key EPSRC prosperity outcomes including a productive, healthy and resilient nation. To foster wider societal impact, the CDT will expect all students to contribute to public outreach and engagement activities including: open days, schools visits, and science festival events: students will participate in an outreach programme, with special focus on widening participation.

This CDT will contribute to the development of industrial strategy through the Synthetic Biology Leadership Council (SBLC), Industrial Biotechnology Leadership Forum (IBLF), and wider Networks in Industrial Biotechnology and Bioenergy and Professional Institutes.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S022856/1 01/04/2019 30/09/2027
2827664 Studentship EP/S022856/1 01/10/2022 30/09/2026 Matthew Jago