Biological beats by a large and a small genome

24-hour biological clocks are nearly ubiquitous amongst eukaryotes, controlling processes from the human sleep-wake cycle to flowering in plants. Linking the clock’s molecular mechanisms to high-level biological functions, timed to appropriate phases of the day/night cycle and the annual cycle of seasons, exemplifies the challenges of multi-scale systems biology. These “circadian” rhythms share similar properties across all organisms, even in some prokaryotes, yet the key ‘clock proteins’, rhythmic transcriptional regulators, are not conserved across taxa.

We are testing the clock circuit in the plant Arabidopsis thaliana, combining molecular and reporter gene timeseries data, with clock mutants and environmental perturbations. The resulting mathematical models of the clock and its output pathways (Biomodels 55, 89, 214, 273, 295, 350, 412, 445) have predicted both particular molecular regulation and operating principles, such as the regulatory flexibility provided by interlocking, negative feedback loops. Testing these hypotheses in the tiny alga Ostreococcus tauri revealed a different strategy to gain flexibility in a tiny genome, using multiple light inputs.

The alga also revealed a clock with a completely different, non-transcriptional mechanism that may be shared from archaea to humans (O’Neill et al. Nature 2011; Edgar et al., Nature 2012). The 133 protein kinases of O. tauri represent a full, unicellular eukaryotic kinome. We are currently testing daily, post-translational regulation by mass spectrometry, revealing rhythmic protein accumulation and phosphorylation, proteome-wide, to identify components and outputs of this clock, which is potentially >2 billion years old.