Molecular Genetics of Biological Clocks

A diverse array of organisms including prokaryotic and eukaryotic microbes, plants, and animals display daily rhythms in physiology, metabolism and/or behavior. These rhythms are not passively driven by environmental cycles of light and temperature, but are actively controlled by endogenous circadian clocks that are set by environmental cycles, keep time in the absence of environmental cues, and activate overt physiological, metabolic and behavioral rhythms at the appropriate time of day. This remarkable conservation of circadian clock function through evolution suggests that maintaining synchrony with the environment is of fundamental importance. Our understanding of the circadian clock is particularly important for human health and well-being. The clearest examples of circadian clock dysfunction are those that result in abnormal sleep-wake cycles, but clock disturbances are also associated with other ailments including epilepsy, cerebrovascular disease, depression, and seasonal affective disorder. The realization that disorders of the sleep-wake cycle such as Familial Advanced Sleep Phase Syndrome can result from alterations in clock gene function underscores the clinical importance of understanding the molecular organization of the circadian system.

Work in my laboratory focuses on defining the molecular mechanisms that drive circadian clock function in the fruit fly, Drosophila melanogaster. We previously found that the core timekeeping mechanism is based on core and interlocked transcriptional feedback loops. Our studies currently focus on (1) defining post-translational regulatory mechanisms that operate in the core loop to set the 24 hour period, (2) determining whether interlocked loops are important for circadian timekeeping and/or output, (3) understanding how circadian oscillator cells are determined during development, and (4) defining mechanisms that control rhythms in olfactory and gustatory physiology and behavior.

1. Yin, JCP, Cui, E, Hardin, PE, Zhou, H. Circadian disruption of memory consolidation in Drosophila. Front Syst Neurosci. 2023;17 :1129152. doi: 10.3389/fnsys.2023.1129152. PubMed PMID:37034015 PubMed Central PMC10073699.
2. Zhang, Y, Iiams, SE, Menet, JS, Hardin, PE, Merlin, C. TRITHORAX-dependent arginine methylation of HSP68 mediates circadian repression by PERIOD in the monarch butterfly. Proc Natl Acad Sci U S A. 2022;119 (4):. doi: 10.1073/pnas.2115711119. PubMed PMID:35064085 PubMed Central PMC8795551.
3. Rivas, GBS, Zhou, J, Merlin, C, Hardin, PE. CLOCKWORK ORANGE promotes CLOCK-CYCLE activation via the putative Drosophila ortholog of CLOCK INTERACTING PROTEIN CIRCADIAN. Curr Biol. 2021;31 (19):4207-4218.e4. doi: 10.1016/j.cub.2021.07.017. PubMed PMID:34331859 PubMed Central PMC8511158.
4. Gunawardhana, KL, Rivas, GBS, Caster, C, Hardin, PE. Crosstalk between vrille transcripts, proteins, and regulatory elements controlling circadian rhythms and development in Drosophila. iScience. 2021;24 (1):101893. doi: 10.1016/j.isci.2020.101893. PubMed PMID:33364582 PubMed Central PMC7753146.
5. Mahesh, G, Rivas, GBS, Caster, C, Ost, EB, Amunugama, R, Jones, R et al.. Proteomic analysis of Drosophila CLOCK complexes identifies rhythmic interactions with SAGA and Tip60 complex component NIPPED-A. Sci Rep. 2020;10 (1):17951. doi: 10.1038/s41598-020-75009-5. PubMed PMID:33087840 PubMed Central PMC7578830.
6. Chatterjee, A, Lamaze, A, De, J, Mena, W, Chélot, E, Martin, B et al.. Reconfiguration of a Multi-oscillator Network by Light in the Drosophila Circadian Clock. Curr Biol. 2018;28 (13):2007-2017.e4. doi: 10.1016/j.cub.2018.04.064. PubMed PMID:29910074 PubMed Central PMC6039274.
7. Fuentes, NR, Mlih, M, Barhoumi, R, Fan, YY, Hardin, P, Steele, TJ et al.. Long-Chain n-3 Fatty Acids Attenuate Oncogenic KRas-Driven Proliferation by Altering Plasma Membrane Nanoscale Proteolipid Composition. Cancer Res. 2018;78 (14):3899-3912. doi: 10.1158/0008-5472.CAN-18-0324. PubMed PMID:29769200 PubMed Central PMC6050089.
8. Siwicki, KK, Hardin, PE, Price, JL. Reflections on contributing to "big discoveries" about the fly clock: Our fortunate paths as post-docs with 2017 Nobel laureates Jeff Hall, Michael Rosbash, and Mike Young. Neurobiol Sleep Circadian Rhythms. 2018;5 :58-67. doi: 10.1016/j.nbscr.2018.02.004. PubMed PMID:31236512 PubMed Central PMC6584674.
9. Gunawardhana, KL, Hardin, PE. VRILLE Controls PDF Neuropeptide Accumulation and Arborization Rhythms in Small Ventrolateral Neurons to Drive Rhythmic Behavior in Drosophila. Curr Biol. 2017;27 (22):3442-3453.e4. doi: 10.1016/j.cub.2017.10.010. PubMed PMID:29103936 .
10. Liu, T, Mahesh, G, Yu, W, Hardin, PE. CLOCK stabilizes CYCLE to initiate clock function in Drosophila. Proc Natl Acad Sci U S A. 2017;114 (41):10972-10977. doi: 10.1073/pnas.1707143114. PubMed PMID:28973907 PubMed Central PMC5642697.