Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 41

metabolome. This approach is important for several reasons. An obvious
provider of many biochemicals in the cell is food. Thereby, the rhythmicity
in energy intake and likely its quality too are critical for the maintenance of
circadian oscillations in chromatin modifications. Food functions as a zeit-
geber for peripheral tissues, specifically, and if food can entrain peripheral
clocks, it is likely that its timekeeping properties have much to do with
its ultimate metabolic effects on chromatin. Studies looking at the role of
the circadian clock in controlling metabolite levels demonstrate that much
of the liver metabolome is under circadian control. Numerous metabolites
oscillate in a circadian fashion, and via studies in Clock knockout animals,
many of these metabolite oscillations have been demonstrated to be depen-
dent directly on the expression of Clock . 75 Bioinformatics techniques which
involve large-scale mining of the literature have been instrumental in map-
ping these circadian metabolites within the context of their cellular sur-
roundings. For example, circadian (and noncircadian) controlled
metabolites are now depicted in interactive maps which incorporate data
from multiple sources to display data on circadian gene oscillation of
metabolite-producing and/or-degrading enzymes, 11 transcription factor
binding sites for these metabolic enzymes, 76,77 and the metabolite's own
interacting metabolites. 75,78-80 These networks can be visualized on an
interactive database, http://circadiomics.igb.uci.edu/ . The circadian oscil-
lation of metabolites includes metabolites representing numerous metabolic
pathways. Amino acid and xenobiotic metabolites tend to be higher at night
in nocturnal rodents, while carbohydrate, lipid, and nucleotide metabolites
peak during the rest phase. 75 While much of the hepatic metabolome is
under circadian influence, studies looking at the metabolome of serum from
humans in which circadian activities (such as sleeping, diurnal eating pat-
terns, and activity) have been removed reveal that a remarkable 15% of
metabolites still oscillate in a circadian fashion. 81 The oscillations of many
amino acid-related metabolites as well as urea cycle metabolites appear to
be tightly linked to the circadian clock and have been reported in several
studies. 75,81-83
The number of oscillatory metabolites that are known to influence various
aspects of clock machinery is growing. For example, a recently discovered
function of the CRY protein depends on rhythmic metabolic factors. Specif-
ically, in Drosophila , CRY controls neuronal firing rate. ILNv neurons, which
are light-sensing neurons of Drosophila pacemaker cells, require CRY for a
rapid light response. 84 This is accomplished via a redox-based flavin mecha-
nism, which induces the CRY-dependent neuronal response to blue light.