Mechanism and evolution of circadian clocks and photoperiodism

The National Institute of General Medical Sciences awarded Vanderbilt University $648,480 on June 12, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support research on the mechanism and evolution of circadian clocks and photoperiodism.

The award funds basic research examining post-translational molecular mechanisms of circadian clocks in bacterial and mammalian model systems. Work will address how biochemical mechanisms sustain long-period (~24 hour) oscillations with precise frequency regulation, the connections between biological clocks and human health (including sleep, alertness, hormones, and metabolism), and how photoperiodic time measurement systems enable seasonally adaptive responses. The research will scrutinize circadian mechanisms in cyanobacteria—the system currently best characterized at the molecular level—with particular focus on temperature compensation through both thermodynamic and metabolic mechanisms. Parallel work in mammalian cells will leverage new data suggesting post-translational circadian capability in those systems.

Performance occurs at Vanderbilt University in Nashville, Tennessee. The award period runs through May 31, 2031. This is a Project Grant, the assistance type used by NIGMS for investigator-initiated biomedical research awards.

Abstract

Biological timekeeping mechanisms such as circadian (daily) rhythms and photoperiodic time measurement (pptm) are fascinating. For circadian rhythms, IT is difficult to explain how a biochemical mechanism can (i) enhance fitness, and (II) robustly sustain a long period (~24 h) oscillation whose frequency keeps time so precisely. Moreover, these rhythms are a crucial component of human health that regulates sleep, alertness, hormones, metabolism, ET AL., but the linkages between biological clocks and health are unclear. For pptm, how does an underlying circadian mechanism measure day/night-length and promote seasonally adaptive responses? Pptm is also relevant to human health in the context of seasonal affective disorders. And how did circadian/pptm timekeeping systems evolve in the first place? These questions remain critically important unanswered issues, especially as therapies based on the principles of chronobiology hold considerable promise for ameliorating human health problems. The johnson laboratory advances a multi- faceted approach, utilizing the most appropriate and advantageous model systems to answer these key questions. This project will address key timekeeping questions in bacterial and mammalian model systems. Post-translational molecular mechanisms of circadian clocks in both bacteria and mammals will be scrutinized. In cyanobacteria, which is the system whose circadian mechanism is currently the best characterized at a molecular level, the ability of these biochemical clocks to maintain a constant period regardless of temperature (the property of "temperature compensation") will be analyzed. A new concept for temperature compensation will be introduced, namely that temperature compensation requires both thermodynamic and metabolic compensation mechanisms. In mammals, exciting new data suggest that mammalian cells are also capable of post-translational circadian rhythms in the absence of any transcriptional/translational feedback loop. Moreover, data from a prior high-throughput screening project will be reanalyzed by machine learning/AI and reinitiated to identify potential chronopharmaceuticals. To better understand the evolution of biological timekeeping, the johnson lab will study both circadian and pptm systems. The discovery of pptm capability in prokaryotes enables new insights into seasonal timekeeping, and this project will analyze in depth the genetic and molecular bases of pptm in cyanobacteria. Related to pptm, the johnson lab has hypothesized that the evolutionary basis of the self-sustained property of circadian rhythms is due to the changing photoperiod over the annual cycle, and this hypothesis will be tested with rigorous competition/selection experiments. Finally, potential selective pressures that are sufficient and necessary to evolve clock properties will be identified by an experimental evolution approach to evolve a clockwork in a "clockless" bacterium, e. Coli. The investigation of these questions/initiatives will lead to wide- ranging discoveries of the mechanisms, applications, and evolution of biological timekeeping.