Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 32

changes in gene expression at relevant loci. Histone 3 (H3) K4 trimethylation
particularly is associated with activation of gene transcription and is essential
for circadian gene transcription and the recruitment of chromatin remodeling
complexes.
Recent high-throughput approaches used in studying the role of the cir-
cadian clock in chromatin structure and function have revealed that mod-
ulation of chromatin structure throughout the circadian period occurs in
a genome-wide way and on a much larger scale than originally appreci-
ated. 17 Specifically, wide scale changes in the circadian regulation of histone
modifications have been observed via RNA-seq experiments with anti-
bodies for H3K4me3, H3K9Ac, and H3K27Ac. These marks show robust
circadian rhythmicity in occupancy near the transcription start sites of many
circadian genes. Interestingly, H3K27Ac is enriched at both intragenic and
intergenic enhancer sites. 17 This and other recent observations underscore
the remarkable ways in which the circadian clock participates in rhythmic
gene expression through the epigenome.
1.1. Histone proteins under circadian control
While the expression of a number of histone modifiers is under circadian
control, 9 some histone modifying proteins directly interact with the circa-
dian clock proteins themselves. For example, enhancer of zeste homology 2
(EZH2), JumonjiC and ARID domain-containing histone lysine
demethylase 1A (JARID1A), histone deacetylase 3 (HDAC3), WD repeat
domain-containing protein 5, mixed-lineage leukemia histone methyl-
transferase 1 (MLL1), and p300/cAMP response element-binding protein
(CREB), p300/CBP all have been reported to bind directly to clock pro-
teins. 18-24 In addition, current studies that are ongoing have begun to
address the rhythmic modification of proteins throughout the circadian
cycle. Specifically, the acetylation of many proteins across the circadian cycle
is oscillatory, allowing rhythmicity in activity even when the expression of
the protein itself remains constant over time. 25 The role of some of these
modifiers and their interaction with the clock machinery will be discussed
further in Sections 1.2-1.4 .
1.2. Histone acetylases under circadian control
As acetylation is a known circadian event at both histone- and
nonchromatin-associated proteins, 25 the expression or activity of several
enzymes that regulate protein acetylation has been studied in a circadian