Circadian regulation of engineered minimal metabolic pathways

Supervisors: Dr Gerben van Ooijen, Prof. Rosalind Allen

Project Description:

Earth’s rotation around its axis causes daily changes to the environment, influencing the metabolism and physiology of organisms since the first life on earth. An endogenous timekeeping mechanism, the circadian clock, evolved to allow anticipation of the daily cycle and drive circadian rhythms such as the sleep-wake cycle in animals or the synthesis and degradation of starch in plants.

In the primary supervisor's lab, we use the experimental model cells of Ostreococcus to efficiently test novel hypotheses that can subsequently be translated into more complex organisms. Ostreococcus is a marine unicellular alga that contains a haploid genome of only ~8000 genes, and a simplistic cellular structure. It is convenient to grow, experimentally highly tractable, and now a well-established circadian clock model organism.

Using comparative approaches, we recently established that clock gene expression rhythms are dispensable for some metabolic rhythms [for an example, see ref 1]. We then identified circadian rhythms in the intracellular concentration of magnesium ions, which determine key clock properties in a unicellular alga, in human cells, and in fungi. Moreover, we found that magnesium rhythms could contribute directly to the rhythmic regulation of cellular metabolism [2].

The novel metabolic circadian rhythms we identified are conserved across eukaryotic life, spanning over a billion years of evolution. Metabolic pathways themselves are also generally shared between all eukaryotes - but it is not clear whether the existing chemical pathways have been evolutionarily selected as optimal, or are instead accidental in design and happened to occur in a very early form of life and have been passed on ever since.

In the second supervisor's lab, an exhaustive in silico search algorithm was recently employed to show that although many alternative pathways exist, the real pathway of glycolysis is the most effective method to produce ATP from glucose [3].

In this project, we will combine strengths in both laboratories, and employ the reduced complexity of Ostreococcus model cells to identify a) the minimal and/or optimal biochemical architecture of metabolic pathways, and b) the exact points of circadian regulation within these pathways. In silico approaches will be combined with gene editing techniques and pharmacological modulations in vivo. The successful candidate will embark on an interdisciplinary project supervised between the Schools of Biology and Physics, and gain a highly diverse training programme in molecular and cellular biology, biochemistry, and biophysics, plus specific experimental design for chronobiology, chemical biology, and synthetic approaches.

1. O’Neill JS, van Ooijen G, Dixon LE, Troein C, Corellou F, Bouget FY, Reddy AB, Millar AJ (2011). Circadian rhythms persist without transcription in a eukaryote. Nature 469: 554-8
2. Feeney KA, Hansen LL, Putker M, Olivares-Yañez C, Day J, Eades LJ, Larrondo LF, Hoyle NP, O'Neill JS, van Ooijen G (2016) Daily magnesium fluxes regulate cellular timekeeping and energy balance. Nature 532: 375-9
3. Court SJ, Waclaw B, Allen RJ (2015) Lower glycolysis carries a higher flux than any biochemically possible alternative. Nature Communications 6: 8427

If you wish to apply for this project, please go to this link.