Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 35

component linking the circadian clock to metabolism. SIRT1 is a class III
HDAC, which differs from the class I and II deacetylases in that it requires
NAD þ . NAD þ serves as a cofactor for SIRT1 and directly modulates its
activity. SIRT1 breaks down NAD þ during lysine deacetylation and pro-
duces O -acetyl-ADP-ribose as a by-product. In the fasting state, levels of
NAD þ rise, and the activity of SIRT1 is elevated as a result. 35 However,
when energy is in excess, NAD þ becomes depleted because of the rampant
flux through the glycolytic cycle which promotes the conversion of NAD þ
to NADH. Recent studies show that SIRT1 directly interacts with circadian
clock machinery and that its rhythmic enzymatic activity is necessary for
robust oscillations in gene expression in vivo . 36,37 The expression of SIRT1
has been reported as oscillatory by some, 38 but the activity of SIRT1 has
been demonstrated to be oscillatory based on the oscillatory abundance of
its cofactor, nucleotide adenine dinucleotide (NAD þ ) as depicted in
Fig. 2.2 . 37,38 SIRT1 is an HDAC for the circadian protein BMAL1 and
it leads to the both the acetylation and degradation of PER2. 38 In addition,
SIRT1 is a chromatin modifier, deacetylating H3K9/14 and thereby
influencing subsequent gene transcription. 39,40
Other HDACs associated with the clock include the protein HDAC3
and its associated nuclear receptor corepressor 1 protein (NCoR1). 41 This
complex is involved in the deacetylation of H3K9 and can dramatically
influence the expression levels of associated genes. HDAC3 has been dem-
onstrated as oscillatory in activity and modulates much of the rhythmic gene
expression that occurs throughout the circadian cycle. 42 Loss of HDAC3
Figure 2.2 The role of SIRT1 in the circadian clock is maintained by NAD þ . The HDAC
SIRT1 associates with CLOCK and BMAL1 proteins at the promoter of some genes,
including those involved in the abundance of its own cofactor, NAD þ . Oscillations in
the recycling of NAD þ by Nampt are perpetuated by rhythmic activation of the Nampt
promoter by CLOCK, BMAL1, and SIRT1.