Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 44

Figure 2.4 The many roles of NAD þ in the cell. As a cofactor for SIRT1 and PARP pro-

teins, NAD þ contributes to rhythmicity in chromatin structure and rhythmic gene
expression. In addition, the mitochondrial role of NAD þ as an electron acceptor is essen-
tial for cellular metabolic homeostasis. Its role as a substrate for cyclic ADP-ribose
(cADPR) modulates intracellular levels of calcium.

receptor oscillation, a number of ligands for these receptors do oscillate in a
circadian fashion and therefore must coordinate with the expression levels of
their corresponding nuclear receptors to correctly time gene expres-
sion. 95-97 Heme is an example of the many nuclear receptor ligands that
appear to be under circadian regulation. Fatty acids, bile acids, prostaglan-
dins, leukotrienes, vitamins, and hormones are also part of the dynamic cir-
cadian metabolome that contributes to circadian physiology via changes in
nuclear receptor activity and expression. 75
In addition to the metabolites mentioned above, several other metabo-
lites have been studies in the context of their role in chromatin remodeling.
Specifically, adenosine triphosphate (ATP) is a potent modulator of chroma-
tin structure as many chromatin remodeling enzymes are ATP dependent. In
Neurospora , the ATP-dependent enzymes Clockswitch (CSW-1/CRF10)
and chromo-domain helicase DNA-binding protein are both required for
oscillations in frq expression. 98
How these metabolites influence circadian function is distinct and prob-
ably tissue specific. A better understanding of how the circadian metabolome