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This response can be attenuated by the administration of an antagonist, which
blocks the flavin binding site in CRY. Interestingly, flavin adenine dinucle-
otide (FAD þ ) is robustly oscillatory in hepatic tissue, and dependent on the
circadian protein CLOCK. 75 Whether flavin oscillates in the Drosophila pace-
maker cells has not been discovered to date; however, light-induced CRY
activity does oscillate in a metabolite-dependent way, and it suggests that there
may be an oscillatory pattern of FAD þ itself. The CLOCK-dependent oscil-
lation of FAD þ in mice suggests that its oscillation may be present in other
tissues and organisms. 75
Another mode of coupling between metabolite availability and the cir-
cadian clock centers on the ability of NPAS2 to function as a gas sensor. 85
Specifically, the PAS domain of the NPAS2 protein can bind heme directly,
allowing it to function as a carbon dioxide-sensitive transcription factor.
Interestingly, there are two enzymes involved in heme and CO biosynthesis,
which are differentially expressed in regions of the brain that highly express
NPAS2, an observation which is likely more than mere coincidence. Ami-
nolevalinic acid synthases ( Alas ), a rate-limiting enzyme in heme biosynthe-
sis, expression is oscillatory in the brain as is the heme oxygenase 2 protein,
which is involved in CO generation. These proteins are expressed robustly
in the same regions that express high levels of NPAS2 as well, particularly the
forebrain. NPAS2 is not solely a heme sensor but appears to be directly reg-
ulated by other metabolites as well. Both heme bound- and nonheme-
bound NPAS2 PAS domains depend on a high NADPH/NADP ratio
for efficient DNA binding. Heme is also a ligand for the circadian protein
REV-ERB a , 86,87 the interaction of which promotes the recruitment of
the NCoR/HDAC3 corepressor complex that leads to the repression of
PGC-1 a expression among other genes. Itself a powerful inducer of heme
synthesis, PGC-1 a can negatively feedback to control the levels of cellular
heme, thereby regulating cellular metabolism. 88 NCoR and the HDAC3
complex get recruited to the promoter of Bmal1 by REV-ERB a , where
they control the expression of Bmal1 . The formation of this complex is
essential for circadian rhythmicity as well as for the oscillation in the expres-
sion of many metabolic genes. 42,89
3.1. The role of specific metabolites in chromatin structure
Studies focused on the oscillatory nature of specific metabolites and their link
to the circadian clock have been revealing in demonstrating how small bio-
chemicals can affect chromatin structure and function. For example, the
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