Analysis of Methyltransferase BUD23 in Energy Metabolism

Lead Research Organisation: University of Oxford
Department Name: RDM Radcliffe Department of Medicine

Abstract

Chronic inflammation is highly prevalent, and underpins the majority of human diseases. Inflammatory signals act on the circadian clock to effect a profound change in the circadian clock machinery, and surprisingly up to five times as many genes show a circadian oscillation in inflamed tissue than in healthy states.
The circadian clock controls up to 25% of metabolic pathways in diverse organ systems, often acting to regulate rate-limiting steps in metabolic cascades. The function of this clock is to permit anticipation of predictable changes in the environment for example sleep/wake cycles with attendant changes from fed to fasted state. Therefore the identification of a major role for inflammation in re-wiring the circadian clock, and altering the coupling of output pathways to clock phase is of major importance.
We propose that an initially adaptive response to inflammation requires regulation of the circadian clock, mediated by cross-talk between core clock components, regulators of energy metabolism, and inflammatory signals, to meet the bioenergetics demands of the inflammatory process. In chronic inflammation this change is maladaptive and imposes a bioenergetic cost, with consequences for inflammatory resolution, organismal energy metabolism, and also in the response to therapeutic
intervention.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
MR/R502236/1 30/09/2017 31/12/2021
1926881 Studentship MR/R502236/1 30/09/2017 30/03/2021
 
Title The role of Bud23 in mouse heart tissue - Cardiac Proteomics 
Description Label-free quantitiative proteomics was performed on murine cardiac tissue in both wildtype and Bud23-knockout animals. The data was deposited in PRIDE, the Proteomics Identifications Database, with the accession code PXD017019. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Gained a large insight into the effects of Bud23 in cardiac tissue, with potential appliactions for mitochondrial disorders and patients with Williams-Beuren Syndrome. This work was published here: https://elifesciences.org/articles/50705 
URL https://www.ebi.ac.uk/pride/archive/projects/PXD017019
 
Description C4X Discovery 
Organisation C4X Discovery Ltd
Country United Kingdom 
Sector Academic/University 
PI Contribution I am currently working on crystallising human Bud23 following our predictive modelling, and additionally will be responsible for all wet lab work going forwards, including biochemical assays.
Collaborator Contribution They have provided software and advise to enable protein modelling of human Bud23, and have assisted us in making contacts to create a biochemical assay, and to crystalise human Bud23. Ultimately, we hope they can assist in creating a biochemical assay with a suitable drug to target Bud23.
Impact We have analysed human Bud23's structure and how it relates to the greater family of methyltransferases. Predictive modelling has given us insight into future pathways we can explore.
Start Year 2017