Carlucci, M.; Oh, E. S.; Silverthorne, T.; Stinchcombe, A. R.; Zelnys, M.; Petronis, A.

Background: During development, the specification of individual cell types requires orchestrated shifts in the activity of thousands of genes, each following precise and coordinated trajectories. The ability of this process to succeed with remarkable reliability, despite its immense complexity, suggests that at least some underlying principles of development are fundamentally simple. Building on recent findings from epigenetic aging research, we hypothesize that linear trajectories in developing cells are influenced by concurrent oscillatory dynamics, which may help ensure synchrony and robustness. Results: Supporting this model, we demonstrate an association between oscillatory and linear dynamics in cytosine modifications in mouse intestinal organoids, as well as in the transcriptomes of C. elegans. Furthermore, we show that transcriptomes of single cells exhibited developmental chrono-heterogeneity, enabling reconstruction of oscillatory cycles which also correlate with linear changes. Conclusions: Oscillation-mediated linear dynamics may represent an evolutionary invention for encoding molecular time and orchestrating developmental processes.