Modelling circadian gene regulation in Arabidopsis thaliana

The circadian clock generates 24-hour biological rhythms, which provide adaptation to the environmental day/night cycle and also allow plants and animals to detect the passing of the seasons, via the day-length (photoperiod) sensor. This project aimed to understand the rhythmic gene circuit in the clock mechanism, and allowed great progress in that area. It built upon intense interest in the molecular genetics of the clock mechanism in the model plant Arabidopsis thaliana, which identified key genes in the regulatory network and validated in vivo reporter methods such as luciferase (LUC) imaging. In 2003, we were beginning to formalise this understanding in mathematical models, which were the most detailed dynamic models of any plant gene network (published in Locke et al. 2005 and 2006, Mol Syst. Biol.).
The aim of this project was to provide experimental materials, protocols and data to support the modelling (3 year PDRA and technician), with a limited amount of theoretical work on data analysis (1 year RA support).
An excellent experimental RA, Kieron Edwards, generated a range of high-quality data that are publicly available online and have been widely used, showing how the circadian clock genes change their expression patterns in different environmental conditions.
The genome-wide data were analysed using a new statistical method, Bayesian Fourier Clustering, from a collaboration with EPSRC funding. Two other statistical or machine learning groups have used the data to develop further methods.
We understood the data only with the help of mathematical models, generated by another collaborator. For example, the key experiment that invalidated the simplest class of plant clock models (Figure 2 of Locke et al. 2005, Mol Syst. Biol.) was prepared and conducted entirely with funding from this project. The data were also crucial in building three further models, published in Locke et al. 2006; Pokhilko et al. 2010 and 2012.
The results have now supported many publications, most immediate were one in Plant Cell and two in Molecular Systems Biology (the Nature journal on Systems Biology). Results from this project also transformed my laboratory's experimental approach to studying the clock, contributed to many later papers, in my lab and in external groups, and contributed to the establishment of Edinburgh's £20M Centre for Systems Biology.
It was challenging work. Some of the simplest experiments revealed unexpected complexity. Our success depended in large part on theoretical research from Maths and Physics, that had to be paid from other funding, which delayed our progress.