How to build a biological clock?

P. NIETO; VERONICA DELGADO; LUIS LARRONDO; C.A. CONDAT

Colonia

Simposio; XV Latin American Symposium on Chronobiology; 2019

Circadian clocks are endogenous timing mechanisms present in most organisms that have evolved independently, at least three times, by convergent evolution. From fungi to mammals, these clocks evolved sharing a functional circuit topology, which relies on the interaction between specific genes, ?clock genes/proteins?, by interlocked transcriptional - translational feedback loops (TTFL). Many TTFL molecular components have been identified in fungi, flies and mammals; however, the crosstalk between clock dynamics and topology is poorly understood. In addition, a growing interest in the field of synthetic biology is to design and build new genetic circuits in cells. Key in these processes is the characterization of the relationship between dynamics and topology of such circuits.Here, we investigated the crosstalk between dynamics and topology of the TTFLs to elucidate which circuit topologies and kinetics promote the emergence of timekeeping mechanisms. By using mathematical models based on ordinary differential equations, we show how the kinetics of certain processes within the TTFL affects delays between clock genes and protein expression and the circadian parameters. We find that period length is sensitive to the combination of mRNA decay, production of the repressor in its active form and its degradation, and these kinetic structures seem conserved when the kinetics of other processes are modified. We compare these theoretical results with data obtained from a synthetic opto-TTFL implemented in budding yeast (Saccharomyces cerevisiae) cells. Our modelling approach allows us to establish a link between the dynamics and topology of TTFLs which is useful for designing and building of genetic clocks.