Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 33

context. A list of several enzymes can be seen in Table 2.1 and includes the
circadian transcription factor CLOCK itself. CLOCK functions dually as a
transcription factor and a histone acetyltransferase, modifying its own binding
partner, BMAL1 by direct acetylation. 26 It also functions as a HAT at the
H3K9/K14 positions. The role of CLOCK as a HAT appears to extend
beyond BMAL1 and H3. CLOCK HAT activity influences gene transcrip-
tion via direct acetylation of nuclear receptors. 27 The discovery that CLOCK
protein functions as a histone acetyltransferase opened up new directions in
our understanding of how this transcriptional activator contributes to such
robust oscillations in gene expression via its binding partner, BMAL1.
Other transcription factor complexes have also been observed to be
potent activators of transcription via both their direct binding to DNA
and their ability to modify chromatin structure. Sometimes,

this is

Table 2.1 Chromatin-modifying enzymes with known association with the circadian
clock
Enzyme Type Targets

p300 Histone

acetyltransferase

H3K9/K14

CREB-binding protein, CBP Histone
acetyltransferase

H3K4

CLOCK Histone

acetyltransferase

H3K9/K14, BMAL1
(ARNTL)

p300/CBP-associated factor,
PCAF

Histone
acetyltransferase

H3K4

SIRT1 Histone deacetylase H3K9, BMAL1, PER2

HDAC3 Histone deacetylase H3K9

MLL1/MLL3 Histone

methyltransferase

H3K4

EZH2 Histone

methyltransferase

H3K27

JARID1A/KDM5 Histone demethylase H3K4

Several factors associated with cAMP-responsive element-binding protein (CREB)-mediated gene tran-
scription as well as the circadian protein CLOCK exhibit acetyltransferase activity. The sirtuin 1 protein
(SIRT1), which associates directly with the clock machinery, and histone deacetylase 3 (HDAC3) both
contain deacetylase activity and are potent regulators of rhythmic transcription. Among the histone
methylases best known for their role in circadian control of gene expression are mixed-lineage leukemia
1 and 3 (MLL1 and MLL3), enhancer of zeste homolog 2 (EZH2), and JumonjiC and ARID domain-
containing histone lysine demethylase 1A (JARID1A).