How to build a biological clock?

NIETO, P. S; DELGADO, V.; CONDAT, C.A.; LARRONDO, L

Colonia

Simposio; XV Latin American Symposium on Chronobiology; 2019

Circadian clocks are endogenous timing mechanisms present in most organisms that have evolved indepen-dently, at least three times, by convergent evolution. From fungi to mammals, these clocks evolved sharinga functional circuit topology, which rely on the interaction between specific genes, ?clock genes/proteins?,by interlocked transcriptional translational feedback loops (TTFL). Many TTFL molecular components havebeen identified in fungi, flies and mammals, however the crosstalk between clock dynamics and topology ispoorly understood. In addition, a growing interest in the field of synthetic biology is to design and build newgenetic circuits in cells. Key in these processes is the characterization of the relationship between dynamicsand topology of such circuits.Here, we investigated the crosstalk between dynamics and topology of the TTFLs to elucidate which circuittopologies and kinetics promote the emergence of timekeeping mechanisms. By using mathematical modelsbased on ordinary differential equations, we show how the kinetics of certain processes within the TTFL af-fects delays between clock genes and protein expression and the circadian parameters. We find that periodlength is sensitive to the combination of mRNA decay, production of the repressor in its active form and itsdegradation, and these kinetic structure seems conserved when the kinetics of other processes are modified.We compare these theoretical results with data obtained from a synthetic opto-TTFL implemented in buddingyeast (Saccharomyces cerevisiae) cells. Our modelling approach allows to establish links between dynamicsand topology of TTFLs which is useful for designing and building of genetic clocks.