Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 36

interaction with NCoR1 eliminates circadian rhythmicity of many clock
genes as well as clock output genes important for cellular metabolism.
1.4. Other histone protein modifiers associated with the
circadian clock
In addition to acetylation as a modifier of histone activity and chromatin
structure, histone protein methylation has been associated with changes
in gene expression. Studies looking at single locus methylation at histone
tails have now been expanded to studies looking at the global changes in this
mark across the genome. These studies reveal not only the importance of this
mark in rhythmic gene transcription but also the complexity of the histone
code during the process of cellular timekeeping.
During a repressive state of circadian gene expression, there is typically
di- and trimethylation of H3K27 at the Per gene locus, a modification that is
dependent on the polycomb group protein, EZH2. 23 At the D-element-
binding protein ( Dbp ) locus, H3K9 acetylation turns into methylation in
a rhythmic fashion, a process that is necessary for the robust changes in
Dbp expression throughout the circadian cycle. 21 H3K4 methylation is
strongly rhythmic and occurs in a circadian manner at numerous rhythmic
genes. Among the histone methyltransferases that participate in the rhythmic
methylation of target genes, the MLL1 protein has been demonstrated as a
protein with potent influence on cellular timekeeping. Specifically, H3K4
methylation by the histone methyltransferase MLL1 is important for circa-
dian gene expression. 20 MLL1, a homolog of Drosophila trithorax, is essen-
tial for cyclic H3K4 trimethylation and functions in a complex with the
CLOCK-BMAL1 heterodimer. MLL1 appears necessary for the develop-
ment of a permissive chromatin state during the process of circadian tran-
scription. In addition to MLL1, the methyltransferase MLL3 also
contributes to circadian transcription. 43 MLL3 is expressed in a circadian
manner, and it is also associated with H3K4me3. Unlike MLL1, it does
not appear to require CLOCK or BMAL1 binding for circadian occupancy,
although it does dramatically affect the expression of numerous core clock
genes. 43 Similar rhythms in H3K4me3 have been observed in Arabidopsis
thaliana , underscoring the role of methyltransferases in the maintenance of
the circadian clock across organisms. 44
The JumonjiC and ARIDdomain-containing histon elysine demethylase
1A (JARID1A, also known as KMD5A) is another histone methyltransferase
implicated in circadian gene expression. JARID1A binds directly to
CLOCK-BMAL1. In addition to its role as a histone demethylase, however,