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How do hybrid two-component systems in gut bacteria regulate global gene expression?

Project Description

One of the major functions of the gut microbiota is its ability to degrade complex carbohydrates from host, dietary and microbial sources. The bacterial genus Bacteroides are experts at this and often encode >300 enzymes in their genome for breaking down these carbohydrates. This project aims to understand the mechanisms by which they sense and respond to specific carbohydrates in the gut. The apparatus that Bacteroides use to degrade polysaccharides is regulated in many cases by a protein known as a Hybrid Two-Component System (HTCS). This transmembrane regulator directly binds to oligosaccharide fragments of a complex polysaccharide in the periplasm, which activates phosphorylation and DNA-binding in the cytoplasm, to upregulate the degradation apparatus. As the sensor, histidine kinase, and DNA binding domain are all present within this single protein, we aim to understand how it is able to regulate global gene expression at the cytoplasmic membrane. Focussing on the heparan sulfate degradation system for which structural and enzymatic data is already known (DOI: 10.1073/pnas.1704367114 and 10.1073/pnas.1200479109) this project in the Lowe and Connolly labs at Newcastle University, and the Cartmell lab at University of Liverpool will fuse cutting edge biochemical, genetic and informatics techniques to understand a question of basic biological importance. The student will first enzymatically generate and purify specific oligosaccharides to activate the HTCS in the Cartmell lab. In Newcastle, they will engineer Bacteroides strains to express epitope-tagged HTCS natively, prior to global DNA binding and transcriptome analysis. Finally, the DNA binding data will be validated by combining classical genetics and innovative microscopy techniques to directly visualise the interactions. The student will be trained in glycobiology, biochemistry, bacterial genetics, and computational analysis of the data generated from next-generation sequencing during these transcriptome studies. The project will reveal novel mechanistic insight into how Bacteroides regulate their glycan degrading machinery, laying the foundations for rational manipulation of strains as potential probiotics.


Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.


Complex N-glycan breakdown by gut Bacteroides involves an extensive enzymatic apparatus encoded by multiple co-regulated genetic loci. Nat Microbiol. (2019) 4:1571-1581

How members of the human gut microbiota overcome the sulfation problem posed by glycosaminoglycans. Proc. Natl. Acad. Sci. USA. (2017) 114:7037-7042

A scissor blade-like closing mechanism implicated in transmembrane signalling in a Bacteroides hybrid two-component system. Proc. Natl. Acad. Sci. USA. (2012) 109:7298-7303

Tuning transcription of nutrient utilization genes to catabolic rate promotes growth in a gut bacterium. Mol Micro. (2014) 94:110-1025

Glycan complexity dictates microbial resource allocation in the large intestine. Nat. Commun. (2015) 6:7481

Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts. PLoS Biol. (2011) 9:e1001221

Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism. Nature (2015) 7533:165

Distinct intra-species virulence mechanisms regulated by a conserved transcription factor. Proc. Natl. Acad. Sci. USA. (2019)

Host-associated niche metabolism controls enteric infection through fine- tuning of type 3 secretion and a co-ordinated suite of effector proteins. Nat Commun (2018) 9:4187

A Highly Conserved Bacterial D-Serine Uptake System Links Host Metabolism and Virulence. PLoS Pathog (2016) 12: e1005359

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