Epigenetic Regulation of the Molecular Clockwork - Progress in Molecular Biology and Translational Science - page 31

number of antisense RNAs, lincRNAs, and microRNAs, underscoring the
pervasive nature of

these modifications in overall cellular circadian

operations. 13
Higher order chromatin structure involves the wrapping of DNA around
histone proteins. Due to the enormous length of DNA strands relative to the
size of a cell, DNA must be packaged extremely tightly. DNA wrapped
around the histone octamer (two copies of each of the histone proteins
H2A, H2B, H3, and H4) is referred to as a nucleosome. Many nucleosomes
packaged together become part of the condensed structure knows as chro-
matin. As chromosomes must be replicated prior to cell division, it is essen-
tial that genes necessary for the development and survival of offspring cells be
replicated. In addition, RNA synthesis requires the binding of additional
polymerase structures which are necessary for initiation and progression
of gene transcription (reviewed in Ref. 14 ) . These processes depend on
priming of the chromatin, a step which involves relaxing of this higher order
structure and unwinding of specific DNA at nucleosomes. This is accom-
plished in part by the modification of histone protein tails, which are essen-
tial components of chromatin structure and function. 15 Modification of
histone tails is essential for providing permissive states for gene transcription.
The ways in which these modifications mediate a permissive state are com-
plex but reveal the importance of generating specific chromatin structures
that allow transcription to occur. During interphase, chromosomes reside
in precise territories which are enveloped by the interchromatin compart-
ment. It is generally thought that gene-dense chromosome territories reside
in the interior regions of the nucleus while regions of the chromosome that
harbor few genes get localized at the nuclear periphery. Specific marks that
occur at histone tails can lead to chromatin decondensation which ultimately
repositions actively transcribed genes out from regions of compact chroma-
tin structures (reviewed in Ref. 16 ) . Some of these histone tail modifications
and their circadian profiles will be addressed below.
Histones contain a number of amino acid residues within their N-terminal
tails that can be modified. These modifications include acetylation, phosphor-
ylation, methylation, sumoylation, ADP-ribosylation, biotinylation, and
ubiquitylation. The type and combination of these modifications are thought
to form a type of “epigenetic code,” a process originally defined by Strahl and
Allis. 8 Alterations at chromatin associated with gene activation typically
include phosphorylation, acetylation, and methylation. Specifically, at the his-
tone 3 tail, phosphorylation at serine 10 (S10), acetylation at lysine 9/14 (K9/
14), and methylation at lysine 4/27 (Me; K4 and K27) often involve robust