Circadian rhythms are oscillations in behavior and physiology that enable organisms to anticipate periodic environmental changes. In mammals, a master pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus orchestrates peripheral oscillators to generate organism-wide rhythmicity. A major role of the circadian system is to temporally orchestrate metabolic processes, including energy homeostasis. Accordingly, circadian dysfunction contributes to human conditions like obesity, diabetes and other traits of metabolic syndrome. Interestingly, the interaction between the circadian system and metabolism is reciprocal. Importantly, feeding cues synchronize peripheral oscillators independent of the SCN by largley unknown mechanisms. Thus, we aim to understand the interplay between metabolism and the circadian clock in mouse liver with a systems biology approach. We have defined a high-quality, whole-genome, 1- hour resolved circadian expression profile from ad lib-fed mice livers. We will next define the murine hepatic transcriptome under controled feeding conditions to study the mutual influence of the metabolic and circadian systems. Specifically, we will: (1) Define the temporal expression profile of murine liver under restricted feeding; Comparison of microarray data from mice fed ad lib with those from mice under a restricted feeding schedule will reveal the impact of feeding time on the hepatic ocillator.(2) Identify transcripts that respond specifically to major food components; Sugars, fats and cholesterol trigger distinct responses. Thus, we will assess the whole-genome hepatic transcriptional changes induced by restricted feeding with specialized food sources and compare them to those of Aim 1. This will reveal how hepatic transcriptional regulation is determined by food composition, timing and the circadian oscillator. (3) Elucidate the relationship between metabolic and circadian regulation of hepatic transcription; We will use expression profiling and bioinformatics approaches to build a regulatory network underlying hepatic gene expression. Transcriptome data from ad lib and restricted-fed Cryptochrome mutant mice will be integrated with available datasets from different transcriptional regulator mouse models to generate regulatory networks. The circadian clock is the biological timing system that determines when biological events, like sleeping and eating, take place. The circadian system is also critical in regulating our metabolism; improper circadian function is linked to human health problems like sleep and mood disorders, as well as metabolic-based conditions like diabetes, insulin-resistance and obesity. Thus, a better understanding of how the circadian clock and metabolism commmunicate will help us find new and improve treatments for these ailments. ? ? ?
| DiTacchio, Luciano; Le, Hiep D; Vollmers, Christopher et al. (2011) Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333:1881-5 |
| Hitomi, Kenichi; DiTacchio, Luciano; Arvai, Andrew S et al. (2009) Functional motifs in the (6-4) photolyase crystal structure make a comparative framework for DNA repair photolyases and clock cryptochromes. Proc Natl Acad Sci U S A 106:6962-7 |
| Vollmers, Christopher; Gill, Shubhroz; DiTacchio, Luciano et al. (2009) Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A 106:21453-8 |
| Baggs, Julie E; Price, Tom S; DiTacchio, Luciano et al. (2009) Network features of the mammalian circadian clock. PLoS Biol 7:e52 |
